Preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereof

ABSTRACT

An alkyl ether derivative represented by the following general formula [1] 
     
       
         
         
             
             
         
       
     
     or its salt: wherein R 1  and R 2  represent each a substituent such as hydrogen, halogeno or alkyl; R 3  represents alkylamino, amino or hydroxyl; the ring A represents a 5- or 6-membered aromatic heterocycle or a benzene ring; m and n are each an integer of from 1 to 6; and p is an integer of from 1 to 3; shows an effect of protecting retinal nerve cells and, therefore, is useful as a preventive and/or a remedy for retinal nerve diseases such as glaucoma, diabetic retinopathy, retinal artery obstruction, retinal venous obstruction, macular degeneration and retinopathy of prematurity.

This is a continuation application of U.S. application Ser. No.10/553,120, filed Oct. 14, 2005, which is a 371 of PCT/JP04/05355 filedon Apr. 14, 2005.

TECHNICAL FIELD

The present invention relates to a preventive and/or remedy for retinalnerve diseases, which comprise a novel alkyl ether derivative or a saltthereof as an active ingredient.

BACKGROUND ART

The retina acting as a photoreceptive tissue is located at the innersurface of the wall of eyeball. When pathologic lesion occurs on theretina, eyesight fails, sometimes resulting in blindness. Such retina isbroadly divided into sensory retina and retinal pigment epithelium. Suchsensory retina is divided into 9 layers, and comprises visual cells asfirst neuron, bipolar cells as second neuron, ganglion cells as thirdneuron, and other cells (Hyojun Ganka Gaku, 7^(th) edition, pp. 103-107,Igaku-Shoin Ltd., 1998).

Various retinal diseases are developed depending on the causes ofdiseases or onset forms. Examples of a disease affecting the retinalnerve may include glaucoma, diabetic retinopathy, retinal arteryobstruction, retinal venous obstruction, macular degeneration, andretinopathy of prematurity.

It has been considered that the cell death of retinal nerve cells isdeeply associated with dysfunction of the retinal nerve. Factors, whichcontribute the cell death of retinal nerve cells, may include apoptosis,neurotoxicity caused by glutamic acid, the absence of a neurotrophicfactor, the abnormality of mitochondria, caspase activation, nitricoxide, and autoimmunity (Atarashii Ganka, 19(7), 903-912, 2002). Forexample, from the viewpoint of suppression of the cell death with anexcitatory neurotransmitter such as glutamic acid, compounds havingantagonistic action to N-methyl-D-aspartic acid have been studied(JP-A-8-506807; Scrip No. 2229, p. 13, 1997; Scrip No. 2307, p. 10,1998).

As stated above, various factors are associated with the cell death ofretinal nerve cells. Other than compounds having antagonistic action toN-methyl-D-aspartic acid, compounds useful as remedies for diseases suchas glaucoma, diabetic retinopathy, retinal artery obstruction, retinalvenous obstruction, macular degeneration, and retinopathy ofprematurity, are required.

DISCLOSURE OF THE INVENTION

The present inventors have found that an alkyl ether derivativerepresented by the general formula [1] described below or a salt thereofshows the effect of protecting retinal nerve cells, and thus that it isuseful as a preventive and/or remedy for retinal nerve diseases, therebycompleting the present invention.

In the formula, R¹ and R², which may be the same or different, eachrepresent one or more groups selected from a hydrogen atom, a halogenatom, a substituted or unsubstituted alkyl, aryl, aralkyl, alkoxy,aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, alkylsulfonyl,arylsulfonyl, carbamoyl or heterocyclic group, a protected orunprotected amino, hydroxyl or carboxyl group, a nitro group and an oxogroup; R³ represents a substituted or unsubstituted alkylamino group ora protected or unprotected amino or hydroxyl group; the ring Arepresents a 5- or 6-membered aromatic heterocyclic ring or a benzenering; m and n each represent an integer between 1 and 6; and prepresents an integer between 1 and 3.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in detail below.

In the present specification, the terms have the following means, unlessotherwise specified.

The term “halogen atom” is used to mean a fluorine atom, a chlorineatom, a bromine atom, or an iodine atom; the term “alkyl group” is usedto mean a linear or branched C₁₋₁₂ alkyl group such as a methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl,or octyl group; the term “lower alkyl group” is used to mean a linear orbranched C₁₋₆ alkyl group such as a methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, or hexyl group; the term “alkenylgroup” is used to mean a C₂₋₁₂ alkenyl group such as a vinyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, or octenyl group; the term “loweralkenyl group” is used to mean a C₂₋₆ alkenyl group such as a vinyl,propenyl, butenyl, pentenyl, or hexenyl group; the term “alkynyl group”is used to mean a C₂₋₆ alkynyl group such as an ethynyl, 2-propynyl, or2-butynyl group; the term “cycloalkyl group” is used to mean acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; the term“alkoxy group” is used to mean a linear or branched C₁₋₁₂ alkyloxy groupsuch as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy group; the term“lower alkoxy group” is used to mean a linear or branched C₁₋₆ alkyloxygroup such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentyloxy, or hexyloxy group; the term “alkenyloxy group”is used to mean a C₂₋₁₂ alkenyloxy group such as a vinyloxy,propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, oroctenyloxy group; the term “lower alkenyloxy group” is used to mean aC₂₋₆ alkenyloxy group such as a vinyloxy, propenyloxy, butenyloxy,pentenyloxy, or hexenyloxy group; the term “alkylthio group” is used tomean a C₁₋₁₂ alkylthio group such as a methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio,pentylthio, hexylthio, heptylthio, or octylthio group; the term “loweralkylthio group” is used to mean a C₁₋₆ alkylthio group such as amethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, tert-butylthio, pentylthio, or hexylthio group; the term“aryl group” is used to mean a phenyl group, naphthyl group, indanylgroup, or indenyl group; the term “aryloxy group” is used to mean aphenyloxy, naphthyloxy, indanyloxy, or indenyloxy group; the term“aralkyl group” is used to mean an ar C₁₋₆ alkyl group such as a benzyl,diphenylmethyl, trityl, or phenethyl group; the term “arylthio group” isused to mean a phenylthio, naphthylthio, indanylthio, or indenylthiogroup; the term “acyl group” is used to mean a formyl group, a C₂₋₁₂alkanoyl group such as acetyl, isovaleryl, propionyl, or pivaloyl, anaralkylcarbonyl group such as benzylcarbonyl, or an aroyl group such asbenzoyl or naphthoyl; the term “alkylsulfonyl group” is used to mean aC₁₋₁₂ alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl,heptylsulfonyl, or octylsulfonyl; the term “lower alkylsulfonyl group”is used to mean a C₁₋₆ alkylsulfonyl group such as methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, orpentylsulfonyl; the term “arylsulfonyl group” is used to mean aphenylsulfonyl, p-toluenesulfonyl, or naphthylsulfonyl group; the term“lower alkylsulfonyloxy group” is used to mean a C₁₋₆ alkylsulfonyloxygroup such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy,isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy,sec-butylsulfonyloxy, tert-butylsulfonyloxy, or pentylsulfonyloxy; theterm “arylsulfonyloxy group” is used to mean a phenylsulfonyloxy,p-toluenesulfonyloxy, or naphthylsulfonyloxy group; the term “alkylaminogroup” is used to mean a mono- or di-C₁₋₆ alkylamino group such asmethylamino, ethylamino, propylamino, isopropylamino, butylamino,dimethylamino, diethylamino, diisopropylamino, or dibutylamino; the term“monoalkylamino group” is used to mean a mono-C₁₋₆ alkylamino group suchas methylamino, ethylamino, propylamino, isopropylamino, or butylamino;the term “dialkylamino group” is used to mean a di-C₁₋₆ alkylamino groupsuch as dimethylamino, diethylamino, diisopropylamino, or dibutylamino;the term “heterocyclic group” is used to mean a heterocyclic groupincluding a 5- or 6-membered ring, condensed ring, or crosslinked ring,containing at least one heteroatom selected from a nitrogen atom, anoxygen atom, and a sulfur atom, such as pyrrolidinyl, piperidinyl,piperazinyl, homopiperazinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, tetrahydroquinolyl, tetrahydroisoquinolyl,quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, quinolyl, quinolizinyl, thiazolyl, tetrazolyl, thiadiazolyl,pyrrolyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl,benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl,benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl,2,3-dihydrobenzopyrrolyl, 2,3-4H-1-thianaphthyl,2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-a]pyridyl,benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl,pyridazinyl, isoindolyl, isoquinolyl, 1,3-benzodioxanyl, or1,4-benzodioxanyl group; and the term “cyclic amino group” is used tomean a cyclic amino group including a 5-, 6-, or 7-membered ring,condensed ring, or crosslinked ring, which contains at least onenitrogen atom as a heteroatom that forms the above ring, and may furthercontain at least one oxygen atom or sulfur atom, such as pyrrolidinyl,piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, orimidazolidinyl.

A 5- or 6-membered aromatic heterocyclic ring as the ring A may be aheterocyclic ring containing one or more heteroatoms selected from anoxygen atom, a nitrogen atom, and a sulfur atom as a heteroatom formingthe above ring. Examples may include 5- or 6-membered aromaticheterocyclic rings such as triazine, pyridazine, pyrimidine, pyrazine,pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole,isoxazole, isothiazole, pyrazole, or pyran.

Substituents for an alkyl group, an aryl group, an aralkyl group, analkoxy group, an aryloxy group, an alkylthio group, an arylthio group,an alkenyl group, an alkenyloxy group, an amino group, an alkylsulfonylgroup, an arylsulfonyl group, a carbamoyl group, and a heterocyclicgroup in R¹ and R², and an alkylamino group in R³, may include a halogenatom, a lower alkyl group, a cycloalkyl group, an aryl group, a loweralkoxy group, an aryloxy group, a lower alkylthio group, an arylthiogroup, a lower alkenyl group, a lower alkylsulfonyl group, anarylsulfonyl group, an alkylamino group, an amino group that may beprotected, a hydroxyl group that may be protected, a carboxyl group thatmay be protected, an acyl group, and a heterocyclic group.

Protecting groups for a carboxyl group may include all groups that canbe used as common protecting groups for a carboxyl group. Examples ofsuch a protecting group may include: a lower alkyl group such as methyl,ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl, or tert-butyl; anaryl group such as phenyl or naphthyl; an ar lower alkyl group such asbenzyl, diphenylmethyl, trityl, 4-nitrobenzyl, 4-methoxybenzyl, orbis(4-methoxyphenyl)methyl; an acyl-lower alkyl group such asacetylmethyl, benzoylmethyl, 4-nitrobenzoylmethyl, 4-bromobenzoylmethyl,or 4-methanesulfonylbenzoylmethyl; an oxygen-containing heterocyclicgroup such as 2-tetrahydropyranyl or 2-teterahydrofuranyl; ahalogeno-lower alkyl group such as 2,2,2-trichloroethyl; a loweralkylsilyl-lower alkyl group such as 2-(trimethylsilyl)ethyl; anacyloxy-lower alkyl group such as acetoxymethyl, propionyloxymethyl, orpivaloyloxymethyl; a nitrogen-containing heterocyclic ring-lower alkylgroup such as phthalimidomethyl or succinimidomethyl; a cycloalkyl groupsuch as cyclohexyl; a lower alkoxy-lower alkyl group such asmethoxymethyl, methoxyethoxymethyl, or 2-(trimethylsilyl)ethoxymethyl;an ar-lower alkoxy-lower alkyl group such as benzyloxymethyl; a loweralkylthio-lower alkyl group such as methylthiomethyl or2-methylthioethyl; an arylthio-lower alkyl group such asphenylthiomethyl; a lower alkenyl group such as 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, or allyl; and a substituted silyl group such astrimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,or tert-butylmethoxyphenylsilyl.

Protecting groups for a hydroxyl group may include all groups that canbe used as common protecting groups for a hydroxyl group. Examples ofsuch a protecting group may include: alkoxy and alkylthio-carbonylgroups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,isobutyloxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl,2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl,1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, orS-benzylthiocarbonyl; an acyl group such as acetyl, formyl,chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,methoxyacetyl, phenoxyacetyl, pivaloyl, or benzoyl; a lower alkyl groupsuch as methyl, tert-butyl, 2,2,2-trichloroethyl, or2-trimethylsilylethyl; a lower alkenyl group such as allyl; a loweralkynyl group such as propargyl; an ar-lower alkyl group such as benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, or trityl;oxygen-containing and sulfur-containing heterocyclic groups such astetrahydrofuryl, tetrahydropyranyl, or tetrahydrothiopyranyl; loweralkoxy- and lower alkylthio-lower alkyl groups such as methoxymethyl,methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,1-ethoxyethyl, or 1-methyl-1-methoxyethyl; lower alkyl- andaryl-sulfonyl groups such as methanesulfonyl or p-toluenesulfonyl; and asubstituted silyl group such as trimethylsilyl, triethylsilyl,triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, diphenylmethylsilyl, ortert-butylmethoxyphenylsilyl.

Protecting groups for an amino group may include all groups that can beused as common protecting groups for an amino group. Examples of such aprotecting group may include: an alkoxycarbonyl group such asmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,1,1-dimethylpropoxycarbonyl, tert-butoxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, 1-adamantyloxycarbonyl, benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,diphenylmethoxycarbonyl, 4-(phenylazo)benzyloxycarbonyl,2-furfuryloxycarbonyl, or 8-quinolyloxycarbonyl; an acyl group such as(mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, phthaloyl, succinyl, alanyl, or leucyl; an ar loweralkyl group such as benzyl, diphenyl, methyl, or trityl; an arylthiogroup such as 2-nitrophenylthio or 2,4-dinitrophenylthio; an alkyl- oraryl-sulfonyl group such as methanesulfonyl or p-toluenesulfonyl; adi-lower alkylamino-lower alkylidene group such asN,N-dimethylaminomethylene; an ar-lower alkylidene group such asbenzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, or2-hydroxy-1-naphthylmethylene; a nitrogen-containing heterocyclicalkylidene group such as 3-hydroxy-4-pyridylmethylene; a cycloalkylidenegroup such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, or3,3-dimethyl-5-oxycyclohexylidene; a diaryl- or diar-loweralkylphosphoryl group such as diphenylphosphoryl or dibenzylphosphoryl;an oxygen-containing heterocyclic alkyl group such as5-methyl-2-oxo-2H-1,3-dioxole-4-yl-methyl; and a substituted silyl groupsuch as trimethylsilyl.

A salt of the compound represented by the general formula [1] mayinclude salts in commonly known basic groups such as an amino group oracidic groups such as a hydroxyl or carboxyl group.

Examples of such salts in basic groups may include: salts with mineralacids such as hydrochloric acid, hydrobromic acid, nitric acid, orsulfuric acid; salts with organic carboxylic acids such as formic acid,acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid,succinic acid, malic acid, tartaric acid, aspartic acid, trichloroaceticacid, or trifluoroacetic acid; and salts with sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, or naphthalenesulfonic acid.

Examples of salts in acidic groups may include: salts with alkalinemetals such as sodium or potassium; salts with alkaline-earth metalssuch as calcium or magnesium; ammonium salts; and salts withnitrogen-containing organic bases such as trimethylamine, triethylamine,tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylmorpholine, diethylamine, dicyclohexylamine, procaine,dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, andN,N′-dibenzylethylenediamine.

Among the aforementioned salts, pharmacologically acceptable salts arepreferable.

When isomers (for example, optical isomers, geometric isomers, andtautomers) are present in the alkyl ether derivative represented by thegeneral formula [1] or a salt thereof, the present invention includesall these isomers, and further includes hydrates, solvates, and allcrystal forms.

Preferred examples of the alkyl ether derivative represented by thegeneral formula [1] or a salt thereof of the present invention may becompounds wherein, the following portion:

is any one of the following (A), (B), and (C):

wherein, preferably, R¹ represents a hydrogen atom; and R² represents ahydrogen atom, a halogen atom or an alkoxy group.

Moreover, the above compound wherein, in general formula [1], m is 2 andn is an integer of 2 or 3, is preferable. Furthermore, the abovecompound wherein, in the above formula, p is an integer of 1 or 2, ismore preferable.

A compound wherein, in the above (A), each of R¹ and R² represents ahydrogen atom; R³ represents a hydroxyl group; m is 2; n is 3; and p is1, is most preferable.

Next, the production method of the alkyl ether derivative represented bythe general formula [1] or a salt thereof will be described.

The alkyl ether derivative represented by the general formula [1] or asalt thereof can be produced by known methods or by appropriatelycombining such methods. For example, it can be produced by the followingproduction method.

wherein R¹, R², R³, A, m, n, and p have the same meanings as definedabove; R^(3a) represents a dialkylamino group, a monoalkylamino groupthat is protected, an amino group that is protected, or a hydroxyl groupthat may be protected; R^(3b) represents a dialkylamino group, amonoalkylamino group that is protected, an amino group that isprotected, or a hydroxyl group that is protected; R^(3c) represents ahydroxyl group that is protected; R^(3d) represents a dialkylaminogroup, a monoalkylamino group, an amino group, or a hydroxyl group; andeach of X¹, X², and X³ represents a leaving group.

Examples of such a leaving group may include a halogen atom, a loweralkylsulfonyloxy group, and an arylsulfonyloxy group.

Next, each production method will be described.

[Production Method 1]

(1-1) The compound represented by the general formula [3] is allowed toreact with the compound represented by the general formula [2] or areactive derivative thereof, so as to produce the compound representedby the general formula [4].

This reaction may be carried out by known methods, for example, by themethod described in Jikken Kagaku Koza, Vol. 22, The Chemical Society ofJapan, pp. 137-173, 1992, (Maruzen), or a method equivalent thereto.

Examples of the reactive derivative of the compound represented by thegeneral formula [2] may include an acid halide, an acid anhydride, anactive amide, and an active ester.

When the compound represented by the general formula [2] is used in theform of a free acid, the reaction is preferably carried out in thepresence of a condensing agent.

Examples of such a condensing agent may include: carbodiimides such asN,N′-dicyclohexylcarbodiimide; halogenating agents such as thionylchloride or oxalyl chloride; acid halides such as ethoxycarbonylchloride; active amidation agents such as carbonyldiimidazole; andazidation agents such as diphenylphosphoric azide.

A condensing agent may be used at a molar ratio to the compoundrepresented by the general formula [2] of 1 or greater:1, and morepreferably between 1:1 and 5:1.

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: water; halogenatedhydrocarbons such as methylene chloride or chloroform; ethers such astetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene,toluene, or xylene; sulfoxides such as dimethyl sulfoxide; amides suchas N,N-dimethylformamide; esters such as ethyl acetate; ketones such asacetone or methyl ethyl ketone; nitriles such as acetonitrile; andheteroaromatics such as pyridine. These solvents may also be used incombination.

This reaction can be carried out in the presence of a base.

Examples of such a base may include organic bases and inorganic bases,such as triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, potassiumtert-butoxide, sodium carbonate, sodium bicarbonate, potassiumcarbonate, or sodium hydroxide.

Such a base is used to the compound represented by the general formula[2] at a molar ratio of 0.5 or greater:1, and preferably at a molarratio between 1:1 and 10:1.

The compound represented by the general formula [3] is used to thecompound represented by the general formula [2] at a molar ratio of 1 orgreater:1, and preferably at a molar ratio between 1:1 and 20:1.

This reaction may be carried out generally between −100° C. and 200° C.,and preferably between −60° C. and 100° C., for 10 minutes to 20 hours.

The obtained compound represented by the general formula [4] maydirectly be used in the subsequent reaction without being isolated.

(1-2) When R^(3a) in the compound represented by the general formula [4]is a hydroxyl group that is not protected, the above compound of thegeneral formula [4] is subjected to a common hydroxyl group-protectingreaction, so as to induce it to the compound represented by the generalformula [4a].

This reaction may be carried out by known methods, for example, by themethod described in Protective Groups in Organic Synthesis, pp. 10-118,1991, Theodora W. Green, John Wiley & Sons, Inc., or a method equivalentthereto.

Examples of a compound used in such a hydroxyl group-protecting reactionmay include: acid anhydrides such as acetic anhydride; acid halides suchas benzoyl chloride, pivaloyl chloride, methoxycarbonyl chloride, orethoxycarbonyl chloride; halides such as methoxymethyl chloride,benzyloxymethyl chloride, benzyl chloride, benzyl bromide, tritylchloride, or triethylsilyl chloride; organic carboxylic acid compoundssuch as benzoic acid; dialkoxyalkyl compounds such as dimethoxymethane;and noncyclic and cyclic alkoxyvinyl compounds such as 2-methoxypropeneor 3,4-dihydro-2H-pyran.

The compound used in a hydroxyl group-protecting reaction is used at amolar ratio to the compound represented by the general formula [4] of 1or greater:1, and preferably between 1:1 and 2:1.

A hydroxyl group-protecting reaction using an acid anhydride, an acidhalide, or a halide, is generally carried out in the presence of a baseor a dehalogenating agent. Examples of a base used herein may includeorganic bases and inorganic bases, such as triethylamine,N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),pyridine, 4-dimethylaminopyridine, potassium tert-butoxide, sodiumhydroxide, potassium hydroxide, or sodium hydride. Examples of adehydrogenating agent may include silver compounds such as silver oxide.

A hydroxyl group-protecting reaction using an organic carboxylic acidcompound is carried out in a dehydrating agent. Examples of adehydrating agent used herein may includetriphenylphosphine-diisopropyl=azodicarboxylate.

In addition, a hydroxyl group-protecting reaction using an acidanhydride, a dialkoxyalkyl compound, or a noncyclic or cyclicalkoxyvinyl compound, is generally carried out in the presence of anacid catalyst. Examples of an acid used herein may include: organicsulfonic acids such as p-toluenesulfonic acid; inorganic acids such ashydrochloric acid or sulfuric acid; and Lewis acids such as borontrifluoride, a boron trifluoride-diethyl ether complex, or a borontrifluoride-tetrahydrofuran complex.

A base, a dehalogenating agent, or a dehydrating agent used in thisreaction may be used at a molar ratio to the compound used in thehydroxyl group-protecting reaction of 1 or greater:1, and preferablybetween 1:1 and 2:1. An acid catalyst may be used at a molar ratio tothe compound represented by the general formula [4] between 0.001:1 and10:1, and preferably between 0.01:1 and 1:1.

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: halogenatedhydrocarbons such as methylene chloride or chloroform; ethers such astetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene,toluene, or xylene; sulfoxides such as dimethyl sulfoxide; amides suchas N,N-dimethylformamide; esters such as ethyl acetate; ketones such asacetone or methyl ethyl ketone; nitriles such as acetonitrile; andheteroaromatics such as pyridine. These solvents may also be used incombination.

This reaction may be carried out generally between −100° C. and 200° C.,and preferably between −60° C. and 100° C., for 10 minutes to 30 hours.

Moreover, the reaction reagent or base used in each of theaforementioned production methods may also be used as a solvent,depending on the properties thereof.

The obtained compound represented by the general formula [4a] may beused in the subsequent reaction without being isolated.

(1-3) The compound represented by the general formula [4] or [4a] issubjected to a common reduction reaction, so as to produce the compoundrepresented by the general formula [1].

This reduction reaction may be carried out by known methods, forexample, by the method described in Shin Jikken Kagaku Koza, Vol. 15,[II], The Chemical Society of Japan, pp. 29-244, 1977, (Maruzen), or amethod equivalent thereto.

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: halogenatedhydrocarbons such as methylene chloride or chloroform; ethers such astetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene,toluene, or xylene; and alcohols such as methanol, ethanol, orisopropanol. These solvents may also be used in combination.

Examples of a reducing agent may include: aluminum hydrides such aslithium aluminum hydride; and boron hydrides such as diborane, aborane-tetrahydrofuran complex, a borane-dimethyl sulfide complex, orsodium borohydride.

When sodium borohydride is used as a reducing agent, the reaction ispreferably carried out in the presence of Lewis acid such as borontrifluoride, a boron trifluoride-diethyl ether complex, or a borontrifluoride-tetrahydrofuran complex.

Such a reducing agent may be used at a molar ratio to the compoundrepresented by the general formula [4] or [4a] of 0.2:1 or greater, andpreferably between 0.5:1 and 10:1.

Lewis acid may be used at a molar ratio to such a reducing agent of 1 orgreater:1, and preferably between 4/3:1 and 2:1.

This reaction may be carried out generally between −50° C. and 200° C.,and preferably between 0° C. and 110° C., for 10 minutes to 20 hours.

[Production Method 2]

The compound represented by the general formula [3] is allowed to reactwith the compound represented by the general formula [5] in the presenceor absence of a base, so as to product the compound represented by thegeneral formula [1a].

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: water; halogenatedhydrocarbons such as methylene chloride or chloroform; aromatichydrocarbons such as benzene, toluene, or xylene; ethers such astetrahydrofuran or dioxane; alcohols such as methanol and ethanol;nitriles such as acetonitrile; amides such as N,N-dimethylformamide;sulfoxides such as dimethyl sulfoxide. These solvents may also be usedin combination.

Examples of a base that is used as necessary may include organic basesand inorganic bases, such as triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, potassiumtert-butoxide, sodium carbonate, sodium bicarbonate, potassiumcarbonate, or sodium hydroxide.

Such a base may be used at a molar ratio to the compound represented bythe general formula [5] of 0.5 or greater:1, and preferably between 1:1and 20:1.

Moreover, this reaction may also be carried out in the presence of acatalyst.

Examples of a catalyst may include potassium iodide and sodium iodide.

Such a catalyst may be used at a molar ratio to the compound representedby the general formula [5] of between 0.01:1 and 10:1, and preferablybetween 0.1:1 and 1:1.

The compound represented by the general formula [3] may be used to thecompound represented by the general formula [5] at a molar ratio of 1 orgreater:1, and preferably at a molar ratio between 1:1 and 20:1.

This reaction may be carried out generally between 0° C. and 200° C.,and preferably between 20° C. and 150° C., for 10 minutes to 20 hours.

Moreover, the reaction reagent or base used in each of theaforementioned production methods may also be used as a solvent,depending on the properties thereof.

[Production Method 3]

The compound represented by the general formula [7] is allowed to reactwith the compound represented by the general formula [6] in the presenceof a base, so as to produce the compound represented by the generalformula [1b].

This reaction may be carried out by known methods, for example, by themethods described in Tetrahedron Letters, Vol. 38, pp. 3251-3254, 1975,and Shin Jikken Kagaku Koza, Vol. 14, [I], The Chemical Society ofJapan, pp. 567-611, 1977, (Maruzen), or methods equivalent thereto.

Examples of a base may include sodium hydride, sodium hydroxide,potassium hydroxide, and potassium tert-butoxide.

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: halogenatedhydrocarbons such as methylene chloride or chloroform; ethers such astetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene,toluene, or xylene; sulfoxides such as dimethyl sulfoxide; amides suchas N,N-dimethylformamide; and water. These solvents may also be used incombination.

This reaction can be carried out in the presence or absence of acatalyst.

Examples of a catalyst used herein may include commonly knownphase-transfer catalysts of quaternary ammonium salts. Preferredexamples may include tetra-n-butyl ammonium hydrogen sulfate andtetra-n-butyl ammonium bromide.

In this reaction, each of the compound represented by the generalformula [7] and a base may be used to the compound represented by thegeneral formula [6] at a molar ratio of 1 or greater:1, and preferablyat a molar ratio between 1:1 and 20:1. A catalyst is used to the abovecompound at a molar ratio between 0.001:1 and 1:1.

This reaction may be carried out generally between −50° C. and 200° C.,and preferably between 0° C. and 150° C., for 10 minutes to 20 hours.

[Production Method 4]

The compound represented by the general formula [9] is allowed to reactwith the compound represented by the general formula [8] in the presenceor absence of a base, so as to produce the compound represented by thegeneral formula [1b].

This reaction may be carried out by known methods, for example, by thesame method as Production method 3.

[Production Method 5]

(5-1) The compound represented by the general formula [1a] or thecompound represented by the general formula [1b] is subjected to acommon deprotection reaction, so as to produce the compound representedby the general formula [1c].

This reaction may be carried out by known methods, for example, by themethod described in Protective Groups in Organic Synthesis, pp. 10-118and 309-405, 1991, Theodora W. Green, John Wiley & Sons, Inc., or amethod equivalent thereto.

This deprotection reaction is carried out, for example, under conditionsconsisting of hydrolysis and transesterification in the presence of anacid or base, substitution and dissociation reaction in the presence ofan acid catalyst, or hydrogenation in the presence of a metal catalyst.Examples of a base used herein may include inorganic bases such assodium hydroxide, potassium hydroxide, or sodium hydride. Examples of anacid used herein may include: organic sulfonic acids such asp-toluenesulfonic acid; organic carboxylic acids such as formic acid,acetic acid, or trifluoroacetic acid; inorganic acids such ashydrochloric acid or sulfuric acid; and Lewis acids such as borontrifluoride, a boron trifluoride-diethyl ether complex, or a borontrifluoride-tetrahydrofuran complex. Examples of a metal catalyst mayinclude transition metals such as platinum, palladium, palladium carbon,or palladium hydroxide.

The base used in this reaction may be used at a molar ratio to thecompound represented by the general formula [1a] or [1b] of 1 orgreater:1, and preferably between 1:1 and 5:1. The acid may be used tothe compound represented by the general formula [1a] or [1b] at a molarratio of 1 or greater:1, and preferably at a molar ratio between 1.1:1and 100:1. In addition, the metal catalyst may be used to the compoundrepresented by the general formula [1a] or [1b] at a catalytic amount,and preferably at a weight ratio between 0.01% and 30%.

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: halogenatedhydrocarbons such as methylene chloride or chloroform; ethers such astetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene,toluene, or xylene; sulfoxides such as dimethyl sulfoxide; amides suchas N,N-dimethylformamide; esters such as ethyl acetate; ketones such asacetone or methyl ethyl ketone; nitriles such as acetonitrile; alcoholssuch as methanol or ethanol; organic carboxylic acids such as formicacid or acetic acid; and water. These solvents may also be used incombination.

This reaction may be carried out generally between −100° C. and 200° C.,and preferably between −60° C. and 120° C., for 10 minutes to 20 hours.

Moreover, the base used in each of the aforementioned production methodsmay also be used as a solvent, depending on the properties thereof.

(5-2) The compound represented by the general formula [1c] is subjectedto a common protection reaction for a hydroxyl group and an amino groupor to an alkylation reaction of an amino group, so as to induce it tothe compound represented by the general formula [1b].

The hydroxyl group-protecting reaction may be carried out by knownmethods, for example, by the method described in Protective Groups inOrganic Synthesis, pp. 10-118, 1991, Theodora W. Green, John Wiley &Sons, Inc., or a method equivalent thereto. This reaction may be carriedout by the same method as in Example (1-2).

The amino group-protecting reaction may be carried out by known methods,for example, by the method described in Protective Groups in OrganicSynthesis, pp. 309-405, 1991, Theodora W. Green, John Wiley & Sons,Inc., or a method equivalent thereto.

Examples of a compound used in the amino group-protecting reaction mayinclude: acid anhydrides such as acetic anhydride; and acid halides suchas acetyl chloride, benzoyl chloride, methanesulfonyl chloride, or tosylchloride. Such a compound may be used at a molar ratio to the compoundrepresented by the general formula [1c] of 1 or greater:1, andpreferably between 1:1 and 2:1.

This reaction is generally carried out in the presence of a base.Examples of such a base may include organic bases and inorganic bases,such as triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, potassiumtert-butoxide, sodium carbonate, sodium bicarbonate, potassiumcarbonate, or sodium hydroxide.

Such a base may be used at a molar ratio to the compound represented bythe general formula [1c] of 0.5 or greater:1, and preferably between 1:1and 10:1.

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: halogenatedhydrocarbons such as methylene chloride or chloroform; ethers such astetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene,toluene, or xylene; sulfoxides such as dimethyl sulfoxide; amides suchas N,N-dimethylformamide; esters such as ethyl acetate; ketones such asacetone or methyl ethyl ketone; nitriles such as acetonitrile; alcoholssuch as methanol or ethanol; and water. These solvents may also be usedin combination.

This reaction may be carried out generally between −100° C. and 200° C.,and preferably between −60° C. and 100° C., for 10 minutes to 20 hours.

Furthermore, an alkylation reaction of an amino group may be carried outby known methods, for example, by the method described in Shin JikkenKagaku Koza, Vol. 14, [III], The Chemical Society of Japan, pp.1332-1399, 1977, (Maruzen), or a method equivalent thereto.

Examples of a compound used in such an alkylation reaction of an aminogroup may include carbonyl compounds such as formalin, paraformaldehyde,acetaldehyde, or acetone.

Such a compound may be used at a molar ratio to the compound representedby the general formula [1c] of 1 or greater:1, and preferably between1:1 and 5:1.

This reaction is generally carried out in the presence of a reducingagent. Examples of a reducing agent may include boron hydrides such assodium borohydride.

Such a reducing agent may be used at a molar ratio to a carbonylcompound of 0.5 or greater:1, and preferably between 1:1 and 10:1.

Any solvent may be used in this reaction, as long as it does not affectthe reaction. Examples of such a solvent may include: water; halogenatedhydrocarbons such as methylene chloride or chloroform; aromatichydrocarbons such as benzene, toluene, or xylene; ethers such astetrahydrofuran or dioxane; and alcohols such as methanol or ethanol.These solvents may also be used in combination.

This reaction may be carried out generally between −100° C. and 200° C.,and preferably between 0° C. and 100° C., for 10 minutes to 30 hours.

The reaction reagent used in each of the aforementioned productionmethods may also be used as a solvent, depending on the propertiesthereof.

In addition, in the aforementioned production methods, the compoundsrepresented by the general formulas [1a], [1b], [1c], [2] to [9], and[4a], can also be used in the form of salts. Examples of such salts arethe same as those of the compound represented by the general formula[1].

When isomers (for example, optical isomers, geometric isomers, andtautomers) are present in the compounds represented by the generalformulas [1a], [1b], [1c], [2] to [9], and [4a], all these isomers canbe used. Further, hydrates, solvates, and all crystal forms can also beused.

Furthermore, the compounds represented by the general formulas [1a],[1b], [1c], [2] to [9], and [4a], may directly be used in the subsequentreaction without being isolated.

When the compounds represented by the general formulas [1], [1a], [1b],[1c], [2] to [9], and [4a], comprise a hydroxyl group, an amino group,or a carboxyl group, such a hydroxyl group, an amino group, or acarboxyl group has previously been protected with a common protectinggroup, and after completion of the reaction, such a protecting group canbe dissociated by known methods, as necessary. Moreover, the alkyl etherderivatives represented by the general formulas [1], [1a], [1b], and[1c], or salts thereof are subjected, for example, to the appropriatecombined use of known methods such as an oxidization reaction, areduction reaction, an alkylation reaction, a halogenation reaction, asulfonylation reaction, a substitution reaction, a dehydration reaction,and a hydrolysis reaction, so as to induce them to another type of alkylether derivative represented by the general formula [1] or a saltthereof.

The thus obtained alkyl ether derivatives represented by the generalformulas [1], [1a], [1b], and [1c], or salts thereof, can be isolatedand purified by common methods such as extraction, crystallization,distillation, or chromatography.

Next, a method for producing the compounds represented by the generalformulas [2] and [5] used as raw materials for producing the compound ofthe present invention will be described.

The compound represented by the general formula [2] can be produced byknown methods or by appropriately combining such methods, for example,by the following production method A.

wherein R¹, R², A, X³, m, and n have the same meanings as defined above;R⁴ represents a cyano group, a lower alkoxycarbonyl group, adialkylaminocarbonyl group, or a cyclic aminocarbonyl group; and X⁴represents a leaving group.(A-1) The compound represented by the general formula [10] is allowed toreact with the compound represented by the general formula [6] in thepresence of a base, so as to produce the compound represented by thegeneral formula [11].

This reaction may be carried out by known methods, for example, by themethod described in Shin Jikken Kagaku Koza, Vol. 14, [I], The ChemicalSociety of Japan, pp. 567-611, 1977, (Maruzen), or a method equivalentthereto.

(A-2) The compound represented by the general formula [12] is allowed toreact with the compound represented by the general formula [8] in thepresence of a base, so as to produce the compound represented by thegeneral formula [11].

This reaction may be carried out by known methods, for example, by thesame method as Production method (A-1).

(A-3) The compound represented by the general formula [11] is subjectedto a common hydrolysis reaction of a nitrile, ester, or amide, so as toproduce the compound represented by the general formula [2]. Thisreaction may be carried out by known methods, for example, by themethods described in Shin Jikken Kagaku Koza, Vol. 14, [II], TheChemical Society of Japan, pp. 930-950, 1977, (Maruzen), and ProtectiveGroups in Organic Synthesis, pp. 152-192, 1981, Theodora W. Green, JohnWiley & Sons. Inc., or methods equivalent thereto.(A-4) The compound represented by the general formula [16] is allowed toreact with the compound represented by the general formula [6] by theMichael addition reaction in the presence of a base, so as to producethe compound represented by the general formula [11a]. This reaction maybe carried out by known methods, for example, by the methods describedin Chemical & Pharmaceutical Bulletin, Vol. 41, pp. 1659-1663, 1993;Shin Jikken Kagaku Koza, Vol. 14, [I], The Chemical Society of Japan,pp. 585-587, 1977, (Maruzen); and JP-A-3-99038, or methods equivalentthereto.(A-5) The compound represented by the general formula [11a] is subjectedto a common hydrolysis reaction of a nitrile, ester, or amide, so as toproduce the compound represented by the general formula [2a]. Thisreaction may be carried out by known methods, for example, by the samemethod as that described in (A-3) above.

The compound represented by the general formula [5] can be produced byknown methods or by appropriately combining such methods, for example,by the following production method B.

wherein R¹, R², X¹, A, m, and n have the same meanings as defined above;R^(4a) represents an alkoxycarbonyl group; R⁵ represents ahydroxyl-protecting group that is stable under basic conditions; each ofX⁵ and X⁶ represents a leaving group.

Examples of a hydroxyl-protecting group that is stable under basicconditions may include: lower alkyl groups such as tert-butyl; loweralkenyl groups such as allyl; ar-lower alkyl groups such as benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, or trityl;oxygen-containing and sulfur-containing heterocyclic groups such astetrahydrofuryl, tetrahydropyranyl, or tetrahydrothiopyranyl; loweralkoxy-lower alkyl groups such as methoxymethyl,2-(trimethylsilyl)ethoxymethyl, or 1-methyl-1-methoxyethyl; andsubstituted silyl groups such as tert-butyldimethylsilyl ordiphenylmethylsilyl.

(B-1) The compound represented by the general formula [13] is allowed toreact with the compound represented by the general formula [6], so as toproduce the compound represented by the general formula [5]. Thisreaction may be carried out by known methods, for example, by themethods described in Tetrahedron Letters, Vol. 38, pp. 3251-3254, 1975,and Shin Jikken Kagaku Koza, Vol. 14, [I], The Chemical Society ofJapan, pp. 567-611, 1977, (Maruzen), or methods equivalent thereto.(B-2) The compound represented by the general formula [14] is allowed toreact with the compound represented by the general formula [6], andthereafter, a protecting group is dissociated, so as to produce thecompound represented by the general formula [15]. This reaction may becarried out by known methods, for example, by the same method asProduction method 3, followed by dissociation of a protecting group.(B-3) The compound represented by the general formula [2] or thecompound represented by the general formula [11b] is subjected to acommon reduction reaction, so as to produce the compound represented bythe general formula [15]. This reduction reaction may be carried out byknown methods, for example, by the method described in Shin JikkenKagaku Koza, Vol. 15, pp. 26-244, 1977, (Maruzen), or a methodequivalent thereto.(B-4) A halogenating agent or a sulfonylating agent is allowed to reactwith the compound represented by the general formula [15] in thepresence or absence of a base, so as to produce the compound representedby the general formula [5].

Examples of a solvent used in this reaction may include: halogenatedhydrocarbons such as methylene chloride or chloroform; ethers such astetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene,toluene, or xylene; sulfoxides such as dimethyl sulfoxide; amides suchas N,N-dimethylformamide; esters such as ethyl acetate; and nitrilessuch as acetonitrile. These solvents may also be used in combination.

In addition, examples of a base used in this reaction as necessary mayinclude organic or inorganic bases, such as triethylamine,diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),pyridine, potassium tert-butoxide, sodium carbonate, potassiumcarbonate, or sodium hydride.

Examples of a halogenating agent may include phosphorus oxychloride,phosphorous oxybromide, phosphorus trichloride, phosphoruspentachloride, carbon tetrabromide-triphenylphosphine, and thionylchloride.

Examples of a sulfonylating agent may include methanesulfonyl chlorideand p-toluenesulfonyl chloride.

Such a halogenating agent, sulfonylating agent, or base may be used tothe compound represented by the general formula [15] at a molar ratio of1 or greater:1, and preferably at a molar ratio between 1:1 and 2:1.

This reaction may be carried out generally between −50° C. and 200° C.,and preferably between 0° C. and 50° C., for 10 minutes to 30 hours.

When the compounds represented by the general formulas [2], [2a], [6],[8], [10] to [16], [11a], and [11b] in the production methods A and B,comprise a hydroxyl group, an amino group, or a carboxyl group, such ahydroxyl group, an amino group, or a carboxyl group has previously beenprotected with a common protecting group, and after completion of thereaction, such a protecting group can be dissociated by known methods,as necessary.

Moreover, when isomers (for example, optical isomers, geometric isomers,and tautomers) are present in the compounds represented by the generalformulas [2], [2a], [6], [8], [10] to [16], [11a], and [11b], all theseisomers can be used. Further, hydrates, solvates, and all crystal formscan also be used.

Furthermore, the compounds represented by the general formulas [2],[2a], [6], [8], [10] to [16], [11a], and [11b], may directly be used inthe subsequent reaction without being isolated.

The compound of the present invention can be formulated intopharmaceutical preparations such as oral agents (a tablet, a capsule, apowder, a granule, a fine granules, a pill, a suspension, an emulsion, asyrup, etc.), injections, or eyedrops, by adding thereto various typesof pharmaceutical additives such as an excipient, a binder, adisintegrator, a disintegration inhibitor, an anticaking/antiadhesionagent, a lubricant, an absorption/adsorption carrier, a solvent, anextender, an isotonizing agent, a solubilizer, an emulsifier, asuspending agent, a thickener, a coating agent, an absorbefacient, agelation/agglutination promoter, a light stabilizer, a preservative, ananti-moisture agent, an emulsion, suspension or dispersion stabilizer, acoloration preventing agent, a deoxidizer/antioxidant, correctives, acoloring agent, a whipping agent, an antifoaming agent, a soothingagent, an antistatic agent, or a buffer/pH adjuster.

The aforementioned various types of agents are formulated by commonmethods.

Oral solid preparations such as a tablet, a powder, or a granule may beprepared according to common methods, using the following pharmaceuticaladditives for such solid preparations, for example: excipients such aslactose, saccharose, sodium chloride, glucose, starch, calciumcarbonate, kaolin, crystalline cellulose, anhydrous dicalcium phosphate,corn starch, or alginic acid; binders such as simple syrup, glucosesolution, starch solution, gelatin solution, polyvinyl alcohol,polyvinylpyrrolidone, shellac, methylcellulose, ethylcellulose, sodiumalginate, gum Arabic, hydroxypropylmethylcellulose,hydroxypropylcellulose, water, or ethanol; disintegrators such as drystarch, alginic acid, agar powders, starch, partial α starch,crosslinked polyvinylpyrrolidone, carboxymethylcellulose, crosslinkedcarboxymethylcellulose sodium, carboxymethylcellulose calcium, or sodiumstarch glycolate; disintegration inhibitors such as stearyl alcohol,stearic acid, cacao butter, or hydrogenated oil; anticaking/antiadhesionagents such as aluminum silicate, calcium hydrogen phosphate, magnesiumoxide, talc, or silicic acid anhydride; lubricants such as carnauba wax,light anhydrous silicic acid, aluminum silicate, magnesium silicate,hardened oil, hardened vegetable oil derivative, sesame oil, whitebeeswax, titanium oxide, dry aluminum hydroxide gel, stearic acid,calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate,sodium lauryl sulfate, or polyethylene glycol; absorption promoters suchas quaternary ammonium salts, sodium lauryl sulfate, urea, or enzyme;and absorption/adsorption carriers such as starch, lactose, kaolin,bentonite, silicic acid anhydride, hydrous silicon dioxide, magnesiumaluminometasilicate, or colloidal silicic acid.

Moreover, as necessary, a tablet may be processed into a tablet coatedwith a common coating agent, such as a sugar-coated tablet, agelatin-coated tablet, a gastric coated tablet, an enteric coatedtablet, and a water-soluble film coated tablet.

A capsule is prepared by mixing the present compound with theaforementioned various types of pharmaceuticals and filling the obtainedmixture in a hard gelatin capsule or soft capsule.

Furthermore, the compound of the present invention may also beformulated into water- or oil-type suspension, solution, syrup, andelixir, by common methods, using the aforementioned various types ofadditives for liquid preparations, such as a solvent, an extender, anisotonizing agent, a solubilizer, an emulsifier, a suspending agent, ora thickener.

An injection may be prepared by common methods, using pharmaceuticaladditives for liquid preparations including: diluents such as water,ethyl alcohol, Macrogol, propylene glycol, citric acid, acetic acid,phosphoric acid, lactic acid, sodium lactate, sulfuric acid, sodiumhydroxide; pH adjusters and buffers, such as sodium citrate, sodiumacetate, or sodium phosphate; stabilizers such as sodium pyrosulfite,ethylenediaminetetraacetic acid, thioglycolic acid, or thiolactic acid;isotonizing agents such as common salts, glucose, mannitol, or glycerin;solubilizers such as carboxymethylcellulose sodium, propylene glycol,sodium benzoate, benzyl benzoate, urethane, ethanolamine, or glycerin;soothing agents such as calcium gluconate, chlorobutanol, glucose, orbenzyl alcohol; and local anesthetics.

An eyedrop may be prepared according to common methods by appropriatelymixing the compound of the present invention with preservatives such aschlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, methyl parahydroxybenzoate, orbenzethonium chloride; buffers such as borax, boric acid, or potassiumdihydrogen phosphate; thickeners such as methylcellulose,hydroxyethylcellulose, carboxymethylcellulose,hydroxypropylmethylcellulose, polyvinyl alcohol, carboxymethylcellulosesodium, or chondroitin sulfate; solubilizers such as polysorbate 80 orpolyoxyethylene hardened caster oil 60; stabilizers such as edetatesodium or sodium bisulfite; or isotonizing agents such as sodiumchloride, potassium chloride, or glycerin.

A method for administration of the aforementioned preparations is notparticularly limited. It is determined as appropriate, depending on theform of a preparation, the age of a patient, the sex thereof, and thedegree of the symptoms of a patient, and other conditions.

The dosage of the active ingredient of the preparation of the presentinvention is selected as appropriate, depending on the usage, the age ofa patient, the sex thereof, the form of disease, and other conditions.In general, the present preparation may be administered at a dosagebetween 0.1 and 500 mg per adult per day, once or divided over severaladministrations.

EXAMPLES

The present invention will be described in the following test example,production examples, and formulation examples. However, these examplesare not intended to limit the scope of the present invention. The mixingratios of eluents in production examples are all represented by volumeratios. The carriers used in column chromatography are B.W. silica gel,BW-127ZH, and FL-100DX (manufactured by Fuji Silysia Chemical Ltd.).

Test Example 1 Protecting Effect of Retinal Nerve in Rat RetinalIschemia Reperfusion Model (a) Preparation of Retinal IschemiaReperfusion Model

A rat retinal ischemia reperfusion model was prepared by a partiallymodified method of Steven Roth et al. (Experimental Eye Research, Vol.65, pp. 771-779, 1997).

As experimental animals, SD rats (SPF, 9-week-old, male, approximately300 g of body weight) were used. Such rats were anesthetized withhalothane (introduction: 4%; retention: 2%; gas composition: 70% air+30%oxygen; gas flow rate: 2 L/min). The rat was placed on a fixing platewith the left body side upward. The skin located between the externalacoustic foramen and the external canthus on the left side was incised,and the skin-incised portion was held with a hook. The temporal musclewas burned out with a bipolar coagulator (output: 4.5 W), and it wasdetached from the cranial bone and the mandibular arch. Thereafter, theoptic nerve was detached under an operation microscope, and the centralretinal blood vessel with the thus obtained optic nerve was tied up witha silk thread to such an extent that the silk thread did not damage theoptic nerve, and thereafter, the silk thread was fixed with a vascularclip. During ischemia for 30 minutes, the incised portion of the rat wasclosed, and the rat was then placed in a cage without undergoinganesthesia, so that it was allowed to move freely. 30 minutes later, thevascular clip and the silk thread were removed under halothaneanesthesia again, so that the blood was allowed to flow again.Thereafter, the incised portion was sutured. In order to prevent theoperated eye (left eye) from infection, ofloxacin eye ointment wasapplied thereto, and the eyelid was sutured in order to prevent thecornea from being dried.

(b) Administration of Test Compound

A test compound dissolved in distilled water was orally administered atan amount of 10 mg/kg to the rat from 2 days after retinal ischemiareperfusion, twice a day, for 14 days. In addition, distilled water wasorally administered to a control group in the same manner describedabove.

(c) Electroretinogram (ERG) Measurement

ERG was measured in accordance with the method of Kawakami et al.(Gifu-dai Iki, Vol. 48, pp. 166-175, 2000). That is to say, afteradaptation to darkness for approximately 1 hour, a mixed solutionconsisting of 66 mg/kg ketamine hydrochloride and 5 mg/kg xylazinehydrochloride was intramuscularly injected into the muscle of thigh ofthe rat for anesthesia under red light. Thereafter, the rat was held onbrain stereotaxis apparatus, and it was further anesthetized by eyedropwith 0.4% oxybuprocaine hydrochloride. Thereafter, contact lenselectrode for ERG was applied thereto. At that time, a droplet ofadjuvant used for application of special contact lens to the cornea wasadded dropwise to the portion between the electrode and the cornea, sothat they were allowed to closely contact with each other. A groundelectrode was implanted into the skin of the lower extremity. For photicstimulation, single-shot white light discharge flashing was applied byfull light emission with a stroboscope (stimulation frequency: 0.017Hz). Such a stroboscope was placed at a position of 10 cm from theanterior surface of cornea of the rat. Electric signals generated as aresult of the photic stimulation were added together twice and thenaveraged using reaction adding/histogram analyzing apparatus. Theobtained waveform was swept on a memory oscilloscope and then recordedby a thermal array recorder. ERG measurement was carried out on eacheye. Since ERG was indicated with the population spike of wave (a) andwave (b), the amplitude value of ERG was defined as a value from thebottom of the wave (a) to the vertex of the wave (b). Such ERGmeasurement was carried out also on a normal control eye of the sameindividual. ERG of the ischemic eye was evaluated as a ratio to thevalue of normal control eye. ERG was measured after adaptation todarkness at 2 days after retinal ischemia reperfusion, and atapproximately 1 hour after the final administration.

(d) Results

The ratio of the ERG amplitude value of the ischemic eye to the normalcontrol eye was 35% in the control group, to which distilled water hadbeen administered. In contrast, the same above ratio was 65% in thegroup, to which1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol maleate.

Production Example 1 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol

(1) 1.20 g of 2-(2-(1-benzothiophene-5-yl)ethoxy)acetic acid wasdissolved in 12 ml of methylene chloride. Thereafter, 2.3 ml oftriethylamine and 0.38 g of imidazole were added to the obtainedsolution, and the mixture was then cooled to 5° C. Thereafter, 0.41 mlof thionyl chloride was added dropwise thereto, and the obtained mixturewas stirred at the same above temperature for 1 hour. The reactionmixture was cooled to −60° C., and thereafter, 0.82 ml of triethylamineand 0.72 g of 3-azetidinol hydrochloride were added thereto. The mixturewas stirred at the same above temperature for 1 hour and then at a roomtemperature for 1.5 hours. Thereafter, water was added to the reactionmixture, and the pH thereof was adjusted to pH 1.0 by addition of 6mol/l hydrochloric acid. Thereafter, an organic layer was separated. Theorganic layer was washed with a saturated saline solution and then driedover anhydrous magnesium sulfate. The solvent was distilled away under areduced pressure, so as to obtain a yellow oil product,2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-ethanone.(2) The above2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-ethanonewas dissolved in 12 ml of tetrahydrofuran, and the obtained solution wascooled to 5° C. Thereafter, 12.7 ml of a tetrahydrofuran solutioncontaining a 1 mol/l borane-tetrahydrofuran complex was added dropwisethereto, and the obtained mixture was stirred at a room temperature for17 hours. Thereafter, 10 ml of acetone was added to the reactionmixture, and the obtained mixture was then stirred for 30 minutes.Thereafter, 6.0 ml of 6 mol/l hydrochloric acid was added thereto,followed by heating to reflux for 2 hours. The reaction solution wascooled, and water and ethyl acetate were added to the reaction mixture.The pH thereof was adjusted to pH 13 by addition of a 2 mol/l aqueoussodium hydroxide solution, and an organic layer was then separated. Theorganic layer was washed with a saturated saline solution and then driedover anhydrous magnesium sulfate. The solvent was distilled away under areduced pressure, so as to obtain 1.13 g of a yellow oil product,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol.

IR (neat)cm⁻¹: 3378, 2943, 1438, 1198, 1119, 703.

NMR (CDCl₃) δppm: 2.66 (2H, t, J=6 Hz), 2.9-3.1 (2H, m), 2.99 (2H, t,J=7 Hz), 3.46 (2H, t, J=6 Hz), 3.6-3.7 (2H, m), 3.67 (2H, t, J=7 Hz),4.41 (1H, qn, J=6 Hz), 7.20 (1H, dd, J=2, 8 Hz), 7.27 (1H, d, J=5 Hz),7.41 (1H, d, J=5 Hz), 7.66 (1H, d, J=2 Hz), 7.78 (1H, d, J=8 Hz).

Production Example 2 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol hydrochloride

1.03 g of 1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol wasdissolved in 4.2 ml of ethyl acetate. Thereafter, 0.86 ml of an ethylacetate solution containing 4.76 mol/l dry hydrogen chloride was addedto the obtained solution, and the obtained mixture was stirred at a roomtemperature for 1 hour, and then at 5° C. for 1 hour. Thereafter,precipitated crystals were collected by filtration, washed with ethylacetate, and then dried, so as to obtain 0.98 g of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol hydrochloride.

Melting point: 101° C. to 102° C.

IR (KBr)cm⁻¹: 3132, 2952, 1423, 1340, 1158, 814, 701.

NMR (CDCl₃) δppm: 2.97 (2H, t, J=7 Hz), 3.2-3.3 (2H, m), 3.69 (2H, t,J=7 Hz), 3.6-3.8 (2H, m), 3.9-4.1 (2H, m), 4.2-4.4 (2H, m), 4.6-4.8 (1H,m), 7.18 (1H, dd, J=1, 8 Hz), 7.29 (1H, d, J=5 Hz), 7.41 (1H, d, J=5Hz), 7.65 (1H, d, J=1 Hz), 7.78 (1H, d, J=8 Hz).

Production Example 3 Production of1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol

1.00 g of 6-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in5 ml of dimethyl sulfoxide. Thereafter, 0.86 g of 3-azetidinolhydrochloride and 1.63 g of potassium carbonate were added to theobtained solution, and the obtained mixture was stirred at 75° C. for2.5 hours, and then at 95° C. for 1.5 hours. Thereafter, the reactionsolution was cooled, and thereafter, water and ethyl acetate were addedto the reaction mixture. The pH of the obtained mixture was adjusted topH 1 by addition of 6 mol/l hydrochloric acid, and a water layer wasthen separated. Ethyl acetate was added to the water layer, and the pHof the obtained mixture was adjusted to pH 10 by addition of a 2 mol/laqueous sodium hydroxide solution, followed by separation of an organiclayer. The organic layer was successively washed with water and asaturated saline solution, and then dried over anhydrous magnesiumsulfate. Thereafter, the solvent was distilled away under a reducedpressure. The residue was purified by column chromatography (eluent;chloroform:methanol=30:1 to 5:1), so as to obtain 0.28 g of anachromatic oil product,1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol.

IR (neat)cm⁻¹: 3398, 2940, 2867, 1197, 1107, 820, 757.

NMR (CDCl₃) δppm: 1.60 (2H, qn, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.7-2.8(2H, m), 2.99 (2H, t, J=7 Hz), 3.45 (2H, t, J=7 Hz), 3.5-3.6 (2H, m),3.66 (2H, t, J=7 Hz), 4.37 (1H, qn, J=6 Hz), 7.23 (1H, dd, J=1, 8 Hz),7.29 (1H, d, J=5 Hz), 7.37 (1H, d, J=5 Hz), 7.73 (1H, d, J=1 Hz), 7.74(1H, d, J=8 Hz).

Production Example 4 Production of1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol hydrochloride

0.28 g of 1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinol wasdissolved in 3.0 ml of ethyl acetate. Thereafter, 0.35 ml of an ethylacetate solution containing 3.25 mol/l dry hydrogen chloride was addedto the obtained solution, and the obtained mixture was stirred at a roomtemperature for 1 hour. Subsequently, the solvent was distilled awayunder a reduced pressure, so as to obtain 0.30 g of a light yellow oilproduct, 1-(3-(2-(1-benzothiophene-6-yl)ethoxy)propyl)-3-azetidinolhydrochloride.

IR (neat)cm⁻¹: 3264, 2866, 2596, 1398, 1109, 1048, 821.

NMR (CDCl₃) δppm: 1.81 (2H, qn, J=6 Hz), 2.92 (2H, t, J=6 Hz), 2.98 (2H,t, J=6 Hz), 3.46 (2H, t, J=6 Hz), 3.68 (2H, t, J=6 Hz), 3.8-3.9 (2H, m),3.8-4.0 (2H, m), 4.4-4.6 (1H, m), 7.23 (1H, dd, J=1, 8 Hz), 7.31 (1H, d,J=5 Hz), 7.39 (1H, d, J=5 Hz), 7.74 (1H, d, J=1 Hz), 7.76 (1H, d, J=8Hz).

Production Example 5 Production of1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol

An achromatic oil product,1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol was obtainedin the same manner as in Production Example 3.

IR (neat)cm⁻¹: 3366, 2942, 2856, 1458, 1436, 1113, 750.

NMR (CDCl₃) δppm: 1.64 (2H, qn=7 Hz), 2.49 (2H, t, J=7 Hz), 2.7-2.8 (2H,m), 3.15 (2H, t, J=7 Hz), 3.50 (2H, t, J=7 Hz), 3.5-3.7 (2H, m), 3.71(2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.06 (1H, s), 7.2-7.4 (2H, m), 7.67(1H, dd, J=1, 7 Hz), 7.77 (1H, dd, J=1, 7 Hz).

Production Example 6 Production of1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol hydrochloride

A light yellow oil product,1-(3-(2-(1-benzothiophene-2-yl)ethoxy)propyl)-3-azetidinol hydrochloridewas obtained in the same manner as in Production Example 4.

IR (neat)cm⁻¹: 3290, 2868, 1457, 1436, 1113, 751.

NMR (CDCl₃) δppm: 1.83 (2H, qn, J=6 Hz), 2.91 (2H, t, J=6 Hz), 3.16 (2H,t, J=6 Hz), 3.52 (2H, t, J=6 Hz), 3.74 (2H, t, J=6 Hz), 3.7-3.8 (2H, m),3.7-3.9 (2H, m), 4.3-4.5 (1H, m), 7.09 (1H, s), 7.27 (1H, dt, J=1, 8Hz), 7.33 (1H, dt, J=1, 8 Hz), 7.69 (1H, dd, J=1, 8 Hz), 7.78 (1H, dd,J=1, 8 Hz).

Production Example 7 Production of1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol

An achromatic oil product,1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol was obtainedin the same manner as in Production Example 3.

IR (neat)cm⁻¹: 3386, 2942, 2856, 1458, 1105, 796, 755, 700.

NMR (CDCl₃) δppm: 1.61 (2H, qn, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.7-2.8(2H, m), 3.17 (2H, t, J=7 Hz), 3.48 (2H, t, J=7 Hz), 3.5-3.7 (2H, m),3.79 (2H, t, J=7 Hz), 4.3-4.5 (1H, m), 7.20 (1H, dd, J=1, 8 Hz), 7.32(1H, t, J=8 Hz), 7.36 (1H, d, J=5 Hz), 7.43 (1H, d, J=5 Hz), 7.70 (1H,dd, J=1, 8 Hz).

Production Example 8 Production of1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol hydrochloride

An achromatic crystal,1-(3-(2-(1-benzothiophene-7-yl)ethoxy)propyl)-3-azetidinol hydrochloridewas obtained in the same manner as in Production Example 2.

Melting point: 105° C. to 106° C.

IR (KBr)cm⁻¹: 3252, 2806, 2620, 1398, 1130, 1106, 811, 708.

NMR (CDCl₃) δppm: 1.82 (2H, qn, J=6 Hz), 2.8-3.0 (2H, m), 3.16 (2H, t,J=6 Hz), 3.47 (2H, t, J=6 Hz), 3.83 (2H, t, J=6 Hz), 3.7-4.1 (4H, m),4.5-4.7 (1H, m), 7.21 (1H, d, J=8 Hz), 7.36 (1H, t, J=8 Hz), 7.38 (1H,d, J=5 Hz), 7.46 (1H, d, J=5 Hz), 7.73 (1H, d, J=8 Hz).

Production Example 9 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol

(1) 5.00 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acid wassuspended in 12.5 ml of toluene, and 0.1 ml of N,N-dimethylformamide wasthen added thereto. Thereafter, 1.68 ml of thionyl chloride was addeddropwise thereto at 15° C., and the obtained mixture was then stirred ata room temperature for 1 hour. This reaction mixture was added dropwiseto 25 ml of an aqueous solution containing 4.44 g of3-hydroxyazetidine-1/2 tartrate and 3.76 g of sodium hydroxide at 10°C., and the mixture was then stirred at a room temperature for 1 hour.Thereafter, ethyl acetate was added to the reaction mixture, so as toseparate an organic layer. The organic layer was successively washedwith diluted hydrochloric acid and a saturated saline solution, and thendried over anhydrous magnesium sulfate. The solvent was then distilledaway under a reduced pressure. The residue was purified by columnchromatography (eluent; chloroform:acetone=3:1 to 1:1), and thencrystallized from diisopropyl ether, so as to obtain 5.48 g of anachromatic crystal,3-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-propanone.

IR (KBr)cm⁻¹: 3316, 2875, 1610, 1481, 1112, 992, 706.

NMR (CDCl₃) δppm: 2.2-2.4 (2H, m), 2.98 (2H, t, J=7 Hz), 3.6-3.8 (5H,m), 3.8-4.0 (1H, m), 4.1-4.3 (2H, m), 4.4-4.4 (1H, m), 7.20 (1H, dd,J=1, 8 Hz), 7.28 (1H, dd, J=1, 5 Hz), 7.41 (1H, d, J=5 Hz), 7.6-7.7 (1H,m), 7.79 (1H, d, J=8 Hz).

(2) 5.00 g of3-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-propanonewas dissolved in 20 ml of tetrahydrofuran, and 1.09 g of sodiumborohydride was then added thereto. Thereafter, 4.25 ml of a borontrifluoride-tetrahydrofuran complex was added dropwise thereto at 10°C., and the obtained mixture was then stirred at the same temperaturefor 1 hour and then at 40° C. for 3 hours. Thereafter, the reactionsolution was cooled to 10° C. Thereafter, 30 ml of 6 mol/l hydrochloricacid was added dropwise to the reaction mixture, followed by reflux for1 hour. After cooling, the solvent was concentrated under a reducedpressure, and ethyl acetate was added thereto. The pH of the mixture wasadjusted to pH 9.4 by addition of a 20% aqueous sodium hydroxidesolution, and an organic layer was then separated. The organic layer wassuccessively washed with water and a saturated saline solution, and thendried over anhydrous magnesium sulfate. The solvent was then distilledaway under a reduced pressure. The residue was purified by columnchromatography (eluent; chloroform:methanol=20:1 to 10:1), and thencrystallized from toluene-diisopropyl ether (1:3; 14 ml), so as toobtain 2.31 g of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol.

IR (KBr)cm⁻¹: 3095, 2944, 2769, 1361, 1191, 1098, 810, 709.

NMR (CDCl₃) δppm: 1.61 (2H, qn, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.7-2.9(2H, m), 2.99 (2H, t, J=7 Hz), 3.45 (2H, t, J=7 Hz), 3.5-3.6 (2H, m),3.66 (2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.22 (1H, dd, J=1, 8 Hz), 7.28(1H, d, J=5 Hz), 7.41 (1H, d, J=5 Hz), 7.67 (1H, d, J=1 Hz), 7.79 (1H,d, J=8 Hz).

Production Example 10 (A) Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol hydrochloride

An achromatic crystal,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinolhydrochloride, was obtained in the same manner as in Production Example2.

Melting point: 71° C. to 73° C.

IR (KBr)cm⁻¹: 3301, 2937, 2809, 2631, 1125, 1099, 818, 765, 710.

NMR (CDCl₃) δppm: 1.8-1.9 (2H, m), 2.98 (2H, t, J=7 Hz), 2.9-3.1 (2H,m), 3.48 (2H, t, J=6 Hz), 3.69 (2H, t, J=7 Hz), 3.6-4.4 (4H, m), 4.5-4.7(1H, m), 7.22 (1H, dd, J=1, 8 Hz), 7.31 (1H, d, J=5 Hz), 7.44 (1H, d,J=5 Hz), 7.68 (1H, d, J=1 Hz), 7.81 (1H, d, J=8 Hz).

(B) Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol 1/2 fumarate

5.00 g of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol wasdissolved in 10.0 ml of ethanol, and the obtained solution was thenheated to 70° C. Thereafter, 0.99 g of fumaric acid was added to thesolution, and the obtained mixture was stirred for 30 minutes.Thereafter, 30.0 ml of ethyl acetate was added dropwise to the solution,and the obtained mixture was stirred at 60° C. for 15 minutes and thencooled to 5° C. over 1 hour. Thereafter, the solution was furtherstirred at the same above temperature for 1 hour. Thereafter,precipitated crystals were collected by filtration and were then washedwith ethyl acetate, followed by drying, so as to obtain 5.83 g of anachromatic crystal,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol 1/2 fumarate.

IR (KBr)cm⁻¹: 3258, 2936, 2862, 1578, 1360, 1114, 1109, 707, 665.

NMR (DMSO-d₆) δppm: 1.5-1.6 (2H, m), 2.60 (2H, t, J=7 Hz), 2.91 (2H, t,J=7 Hz), 2.9-3.1 (2H, m), 3.39 (2H, t, J=7 Hz), 3.60 (2H, t, J=7 Hz),3.6-3.8 (2H, m), 4.1-4.3 (1H, m), 6.50 (1H, s), 7.25 (1H, dd, J=1, 8Hz), 7.39 (1H, d, J=5 Hz), 7.72 (1H, d, J=5 Hz), 7.73 (1H, d, J=1 Hz),7.89 (1H, d, J=8 Hz).

(C) Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol maleate

8.00 g of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol wasdissolved in 56 ml of acetone. Thereafter, 3.19 g of maleic acid wasadded thereto, and the obtained mixture was heated to 60° C. fordissolution. The reaction mixture was gradually cooled, and it was thenstirred at 5° C. for 30 minutes. Thereafter, precipitated crystals werecollected by filtration, so as to obtain 9.89 g of an achromaticcrystal, 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinolmaleate.

NMR (DMSO-d₆) δppm: 1.6-1.8 (2H, m), 2.93 (2H, t, J=7 Hz), 3.13 (2H, t,J=7 Hz), 3.43 (2H, t, J=6 Hz), 3.63 (2H, t, J=7 Hz), 3.7-3.9 (2H, m),4.1-4.3 (2H, m), 4.4-4.5 (1H, m), 6.04 (2H, s), 7.26 (1H, dd, J=1, 8Hz), 7.40 (1H, d, J=5 Hz), 7.7-7.8 (1H, m), 7.74 (1H, d, J=5 Hz), 7.92(1H, d, J=8 Hz).

Production Example 11 Production of1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol

An achromatic oil product,1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol was obtainedin the same manner as in Production Example 3.

IR (neat)cm⁻¹: 3368, 2946, 2856, 1457, 1107, 759.

NMR (CDCl₃) δppm: 1.60 (2H, qn, J=7 Hz), 2.44 (2H, t, J=7 Hz), 2.7-2.9(2H, m), 3.22 (2H, t, J=7 Hz), 3.45 (2H, t, J=7 Hz), 3.5-3.6 (2H, m),3.70 (2H, t, J=7 Hz), 4.3-4.5 (1H, m), 7.19 (1H, d, J=7 Hz), 7.28 (1H,t, J=7 Hz), 7.44 (1H, d, J=6 Hz), 7.46 (1H, d, J=6 Hz), 7.76 (1H, d, J=7Hz).

Production Example 12 Production of1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol hydrochloride

A light yellow oil product,1-(3-(2-(1-benzothiophene-4-yl)ethoxy)propyl)-3-azetidinol hydrochloridewas obtained in the same manner as in Production Example 4.

IR (neat)cm⁻¹: 3302, 2966, 2877, 2594, 1412, 1108, 766.

NMR (CDCl₃) δppm: 1.78 (2H, qn, J=6 Hz), 2.82 (2H, t, J=7 Hz), 3.21 (2H,t, J=6 Hz), 3.43 (2H, t, J=6 Hz), 3.73 (2H, t, J=6 Hz), 3.7-3.9 (2H, m),3.8-4.0 (2H, m), 4.5-4.7 (1H, m), 7.21 (1H, d, J=7 Hz), 7.30 (1H, t, J=7Hz), 7.49 (2H, s), 7.78 (1H, d, J=7 Hz).

Production Example 13 Production of1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol

1.00 g of 3-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in5 ml of dimethyl sulfoxide. Thereafter, 1.10 g of 3-azetidinoltrifluoroacetate and 1.63 g of potassium carbonate were added to theobtained solution, and the mixture was then stirred at 70° C. for 2hours. After cooling, water and ethyl acetate were added to the reactionmixture. The pH of the mixture was adjusted to pH 1 by addition of 6mol/l hydrochloric acid, and a water layer was then separated. Ethylacetate was added to the water layer, and the pH of the obtained mixturewas adjusted to pH 10 by addition of a 2 mol/l aqueous sodium hydroxidesolution, followed by separation of an organic layer. The organic layerwas successively washed with water and a saturated saline solution, andthen dried over anhydrous magnesium sulfate. Thereafter, the solvent wasdistilled away under a reduced pressure. The residue was purified bycolumn chromatography (eluent; chloroform:methanol=30:1 to 10:1), so asto obtain 0.55 g of an achromatic oil product,1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol.

IR (neat)cm⁻¹: 3368, 2942, 2845, 1427, 1191, 1109, 759.

NMR (CDCl₃) δppm: 1.62 (2H, qn, J=7 Hz), 2.47 (2H, t, J=7 Hz), 2.7-2.9(2H, m), 3.11 (2H, t, J=7 Hz), 3.48 (2H, t, J=6 Hz), 3.5-3.7 (2H, m),3.74 (2H, t, J=7 Hz), 4.3-4.5 (1H, m), 7.18 (1H, s), 7.33 (1H, dt, J=1,7 Hz), 7.39 (1H, dt, J=1, 7 Hz), 7.77 (1H, dd, J=1, 7 Hz), 7.86 (1H, dd,J=1, 7 Hz).

Production Example 14 Production of1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol hydrochloride

A light yellow oil product,1-(3-(2-(1-benzothiophene-3-yl)ethoxy)propyl)-3-azetidinol hydrochloridewas obtained in the same manner as in Production Example 4.

IR (neat)cm⁻¹: 3284, 2966, 2596, 1428, 1112, 1049, 765, 734.

NMR (CDCl₃) δppm: 1.83 (2H, qn, J=6 Hz), 2.96 (2H, t, J=6 Hz), 3.12 (2H,t, J=6 Hz), 3.48 (2H, t, J=6 Hz), 3.76 (2H, t, J=6 Hz), 3.8-3.9 (2H, m),3.9-4.1 (2H, m), 4.5-4.7 (1H, m), 7.21 (1H, s), 7.35 (1H, dt, J=1, 7Hz), 7.40 (1H, dt, J=1, 7 Hz), 7.78 (1H, dd, J=1.7 Hz), 7.86 (1H, dd,J=1, 7 Hz).

Production Example 15 Production ofN-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinyl)acetamide

0.80 g of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in8 ml of N,N-dimethylformamide. Thereafter, 1.20 g ofN-(3-azetidinyl)acetamide was added to the obtained solution, and theobtained mixture was stirred at 90° C. for 12 hours. After cooling,water and ethyl acetate were added to the reaction mixture, and anorganic layer was separated. The organic layer was successively washedwith water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. Thereafter, the solvent was distilled awayunder a reduced pressure. The residue was purified by columnchromatography (eluent; chloroform:methanol=7:1), so as to obtain 0.39 gof a light yellow oil product,N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinyl)acetamide.

IR (neat)cm⁻¹: 3276, 2941, 2860, 1654, 1559, 1111, 756, 703.

NMR (CDCl₃) δppm: 1.59 (2H, qn, J=7 Hz), 1.97 (3H, s), 2.42 (2H, t, J=7Hz), 2.7-2.9 (2H, m), 2, 98 (2H, t, J=7 Hz), 3.45 (2H, t, J=7 Hz),3.4-3.6 (2H, m), 3.66 (2H, t, J=7 Hz), 4.4-4.5 (1H, m), 7.22 (1H, dd,J=1, 8 Hz), 7.29 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H, d, J=1Hz), 7.80 (1H, d, J=8 Hz).

Production Example 16 Production of1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol

(1) 0.74 g of 2-(2-(1-benzothiophene-6-yl)ethoxy)acetic acid wasdissolved in 7.4 ml of methylene chloride. Thereafter, 1.36 ml oftriethylamine and 0.22 g of imidazole were added to the obtainedsolution. Subsequently, the mixture was cooled to 5° C. Thereafter, 0.24ml of thionyl chloride was added dropwise thereto, and the obtainedmixture was stirred at the same above temperature for 1 hour. After thereaction mixture was cooled to −50° C., 0.45 ml of triethylamine and0.32 ml of 3-pyrrolidinol were added thereto. The mixture was stirred atthe same above temperature for 1 hour and then at a room temperature for1 hour. Thereafter, water was added to the reaction mixture, and anorganic layer was separated. The organic layer was successively washedwith 1 mol/l hydrochloric acid, then with a 2 mol/l aqueous sodiumhydroxide solution, and then with a saturated saline solution. Theresultant was then dried over anhydrous magnesium sulfate. Subsequently,the solvent was distilled away under a reduced pressure, so as to obtaina light yellow oil product,2-(2-(1-benzothiophene-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone.

IR (neat)cm⁻¹: 3386, 2942, 1636, 1106, 758.

(2) The above2-(2-(1-benzothiophene-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas dissolved in 7.4 ml of tetrahydrofuran. Thereafter, 7.4 ml of atetrahydrofuran solution containing a 1 mol/l borane-tetrahydrofurancomplex was added dropwise to the obtained solution while cooling onice, and the obtained mixture was then stirred at a room temperature for17 hours. Thereafter, 10 ml of acetone was added to the reactionmixture, and the obtained mixture was then stirred for 30 minutes.Thereafter, 1.5 ml of 6 mol/l hydrochloric acid was added thereto, andthe obtained mixture was heated to reflux for 2 hours. After thereaction mixture was cooled, water and ethyl acetate were added thereto,and a water layer was separated. Thereafter, ethyl acetate was added tothe water layer. The pH of the obtained mixture was adjusted to pH 9.5by addition of a 2 mol/l aqueous sodium hydroxide solution, followed byseparation of an organic layer. The organic layer was successivelywashed with water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. Thereafter, the solvent was distilled awayunder a reduced pressure. The residue was purified by columnchromatography (eluent; chloroform:methanol=30:1 to 20:1), so as toobtain 0.53 g of a yellow oil product,1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol.

IR (neat)cm⁻¹: 3386, 2940, 2867, 1110, 820, 756.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.0-2.2 (1H, m), 2.31 (1H, dt, J=7, 9Hz), 2.53 (1H, dd, J=5, 10 Hz), 2.6-2.7 (3H, m), 2.85 (1H, dt, J=5, 9Hz), 3.01 (2H, t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz),4.2-4.3 (1H, m), 7.23 (1H, d, J=8 Hz), 7.29 (1H, d, J=5 Hz), 7.37 (1H,d, J=5 Hz), 7.73 (1H, d, J=8 Hz), 7.73 (1H, s).

Production Example 17 Production of1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

0.48 g of 1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinolwas dissolved in 2.0 ml of ethyl acetate. Thereafter, 2.8 ml of an ethylacetate solution containing 0.15 g of oxalic acid was added to theobtained solution, and the mixture was stirred at a room temperature for1 hour and then at 5° C. for 1 hour. Thereafter, precipitated crystalswere collected by filtration and were then washed with ethyl acetate,followed by drying, so as to obtain 0.42 g of an achromatic crystal,1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate.

IR (KBr)cm⁻¹: 3384, 2862, 2687, 1717, 1636, 1400, 1200, 1114, 720.

NMR (DMSO-d₆) δppm: 1.7-1.8 (1H, m), 1.9-2.1 (1H, m), 2.96 (2H, t, J=7Hz), 3.0-3.2 (1H, m), 3.1-3.4 (5H, m), 3.6-3.8 (4H, m), 4.3-4.4 (1H, m),7.29 (1H, d, J=8 Hz), 7.41 (1H, d, J=5 Hz), 7.68 (1H, d, J=5 Hz), 7.80(1H, d, J=8 Hz), 7.87 (1H, s).

Production Example 18 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol

2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Production Example 16(1).

NMR (CDCl₃) δppm: 1.6-2.2 (2H, m), 2.9-4.0 (8H, m), 4.0-4.2 (2H, m),4.2-4.5 (1H, m), 7.1-7.4 (2H, m), 7.42 (1H, d, J=5 Hz), 7.69 (1H, s),7.79 (1H, d, J=8 Hz).

Subsequently, a light yellow oil product,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol was obtainedin the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3386, 2941, 2864, 1438, 1112, 755, 702.

NMR (CDCl₃) δppm: 1.5-2.0 (1H, m), 2.0-2.9 (7H, m), 3.00 (2H, t, J=7Hz), 3.58 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.21(1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H,s), 7.79 (1H, d, J=8 Hz).

Production Example 19 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate wasobtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3347, 2943, 2687, 1719, 1404, 1119, 720.

NMR (CDCl₃) δppm: 1.7-2.2 (2H, m), 2.9-3.8 (6H, m), 2.94 (2H, t, J=6Hz), 3.68 (4H, t, J=6 Hz), 4.2-4.5 (1H, m), 7.17 (1H, d, J=8 Hz), 7.26(1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.62 (1H, s), 7.78 (1H, d, J=8Hz).

Production Example 20 Production of1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinol

An oil product,2-(2-(1-benzothiophene-4-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Production Example 16(1).

IR (neat)cm⁻¹: 3374, 2944, 1637, 1107, 761.

Subsequently, a light yellow oil product,1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinol was obtainedin the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3376, 2939, 2867, 1452, 1413, 1111, 760.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.30 (1H, dt, J=6, 9Hz), 2.53 (1H, dd, J=5, 10 Hz), 2.6-2.7 (3H, m), 2.85 (1H, dt, J=5, 9Hz), 3.25 (2H, t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.75 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 7.20 (1H, d, J=7 Hz), 7.27 (1H, t, J=7 Hz), 7.44 (1H,d, J=6 Hz), 7.46 (1H, d, J=6 Hz), 7.75 (1H, d, J=7 Hz).

Production Example 21 Production of1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride

0.63 g of 1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinolwas dissolved in 5.0 ml of ethyl acetate. Thereafter, 0.80 ml of anethyl acetate solution containing 3.25 mol/l dry hydrogen chloride wasadded to the obtained solution. The mixture was stirred at a roomtemperature for 1 hour and then at 5° C. for 1 hour. Thereafter,precipitated crystals were collected by filtration. The precipitatedcrystals were washed with ethyl acetate and then dried, so as to obtain0.43 g of an achromatic crystal,1-(2-(2-(1-benzothiophene-4-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride.

IR (KBr)cm⁻¹: 3229, 2872, 2625, 1451, 1413, 1119, 771.

NMR (DMSO-d₆) δppm: 1.7-2.2 (2H, m), 2.9-3.6 (6H, m), 3.22 (2H, t, J=7Hz), 3.74 (4H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.27 (1H, d, J=8 Hz), 7.30(1H, t, J=8 Hz), 7.61 (1H, d, J=5 Hz), 7.77 (1H, d, J=5 Hz), 7.86 (1H,d, J=8 Hz).

Production Example 22 Production of1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinol

An oil product,2-(2-(1-benzothiophene-7-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Example 16(1).

NMR (CDCl₃) δppm: 1.8-2.0 (2H, m), 3.1-3.3 (3H, m), 3.3-3.6 (3H, m),3.8-4.0 (2H, m), 4.0-4.2 (2H, m), 4.3-4.5 (1H, m), 7.23 (1H, d, J=7 Hz),7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 7.6-7.8 (1H, m).

Subsequently, an achromatic oil product,1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinol was obtainedin the same manner as in Example 16(2).

IR (neat)cm⁻¹: 3385, 2941, 2867, 1459, 1395, 1106, 795, 754, 701.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.30 (1H, dt, J=7, 9Hz), 2.52 (1H, dd, J=5, 10 Hz), 2.6-2.7 (3H, m), 2.85 (1H, dt, J=5, 9Hz), 3.19 (2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz), 3.84 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 7.20 (1H, d, J=8 Hz), 7.32 (1H, t, J=8 Hz), 7.35 (1H,d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.69 (1H, d, J=8 Hz).

Production Example 23 Production of1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride

An achromatic crystal,1-(2-(2-(1-benzothiophene-7-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride was obtained in the same manner as in Production Example21.

IR (KBr)cm⁻¹: 3283, 2938, 2706, 1395, 1358, 1125, 810, 720.

NMR (DMSO-d₆) δppm: 1.7-2.2 (2H, m), 2.8-3.7 (6H, m), 3.12 (2H, t, J=7Hz), 3.7-3.8 (2H, m), 3.82 (2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.29 (1H,d, J=7 Hz), 7.36 (1H, t, J=7 Hz), 7.49 (1H, d, J=5 Hz), 7.76 (1H, d, J=5Hz), 7.77 (1H, d, J=7 Hz).

Production Example 24 Production of1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol

2-(2-(1-benzothiophene-2-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Example 16 (1).

NMR (CDCl₃) δppm: 1.8-2.0 (2H, m), 3.1-3.3 (3H, m), 3.3-3.7 (3H, m),3.8-4.0 (2H, m), 4.1-4.2 (2H, m), 4.2-4.5 (1H, m), 7.10 (1H, s), 7.2-7.4(2H, m), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m).

Subsequently, a light yellow oil product,1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol was obtainedin the same manner as in Example 16(2).

IR (neat)cm⁻¹: 3396, 2939, 1458, 1438, 1113, 747, 727.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.34 (1H, dt, J=6, 9Hz), 2.55 (1H, dd, J=5, 10 Hz), 2.6-2.8 (3H, m), 2.85 (1H, dt, J=5, 9Hz), 3.18 (2H, dt, J=1, 7 Hz), 3.62 (2H, t, J=6 Hz), 3.77 (2H, t, J=7Hz), 4.2-4.4 (1H, m), 7.07 (1H, s), 7.26 (1H, dt, J=1, 8 Hz), 7.31 (1H,dt, J=1, 8 Hz), 7.67 (1H, dd, J=1, 8 Hz), 7.76 (1H, dd, J=1, 8 Hz).

Production Example 25 Production of1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal,1-(2-(2-(1-benzothiophene-2-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate wasobtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3432, 2871, 1716, 1436, 1127, 827, 760, 706.

NMR (DMSO-d₆) δppm: 1.7-1.8 (1H, m), 1.9-2.2 (1H, m), 3.0-3.4 (8H, m),3.73 (4H, t, J=6 Hz), 4.2-4.4 (1H, m), 7.23 (1H, s), 7.28 (1H, t, J=7Hz), 7.33 (1H, t, J=7 Hz), 7.74 (1H, d, J=7 Hz), 7.87 (1H, d, J=7 Hz).

Production Example 26 Production of1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol

An oil product,2-(2-(1-benzothiophene-3-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Example 16(1).

NMR (CDCl₃) δppm: 1.8-1.9 (1H, m), 1.9-2.0 (1H, m), 3.1-3.6 (6H, m),3.8-4.0 (2H, m), 4.09 (1H, s), 4.13 (1H, s), 4.3-4.5 (1H, m), 7.26 (1H,s), 7.3-7.4 (2H, m), 7.77 (1H, d, J=8 Hz), 7.85 (1H, d, J=8 Hz).

Subsequently, a light yellow oil product,1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol was obtainedin the same manner as in Example 16(2).

IR (neat)cm⁻¹: 3388, 2934, 1426, 1112, 761, 733.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.33 (1H, dt, J=6, 9Hz), 2.56 (1H, dd, J=5, 10 Hz), 2.6-2.8 (3H, m), 2.87 (1H, dt, J=5, 9Hz), 3.14 (2H, dt, J=1, 7 Hz), 3.61 (2H, t, J=6 Hz), 3.80 (2H, t, J=7Hz), 4.3-4.4 (1H, m), 7.20 (1H, s), 7.34 (1H, dt, J=1, 7 Hz), 7.38 (1H,dt, J=1, 7 Hz), 7.77 (1H, dd, J=1, 7 Hz), 7.85 (1H, dd, J=1, 7 Hz).

Production Example 27 Production of1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal,1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate wasobtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3363, 2922, 2691, 1718, 1636, 1427, 1404, 1119, 767, 721.

NMR (DMSO-d₆) δppm: 1.7-1.8 (1H, m), 2.0-2.2 (1H, m), 3.10 (2H, t, J=7Hz), 3.1-3.4 (6H, m), 3.72 (2H, t, J=5 Hz), 3.78 (2H, t, J=7 Hz),4.3-4.4 (1H, m), 7.37 (1H, t, J=8 Hz), 7.42 (1H, t, J=8 Hz), 7.51 (1H,s), 7.85 (1H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz).

Production Example 28 Production of1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinol

A yellow oil product,2-(2-(1-naphthyl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone wasobtained in the same manner as in Production Example 16(1).

IR (neat)cm⁻¹: 3392, 2946, 1645, 1133, 800, 779.

Subsequently, a light yellow oil product,1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinol was obtained in thesame manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3395, 2944, 1107, 778.

NMR (CDCl₃) δppm: 1.5-1.9 (1H, m), 2.0-2.5 (3H, m), 2.5-3.0 (4H, m),3.37 (2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz), 3.80 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 7.4-7.6 (4H, m), 7.6-8.0 (2H, m), 8.0-8.2 (1H, m).

Production Example 29 Production of1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal, 1-(2-(2-(1-naphthyl)ethoxy)ethyl)-3-pyrrolidinoloxalate was obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3366, 1400, 1116, 780, 720.

NMR (DMSO-d₆) δppm: 1.6-2.3 (2H, m), 2.7-3.5 (8H, m), 3.5-3.9 (4H, m),4.2-4.5 (1H, m), 7.4-7.6 (4H, m), 7.7-8.0 (2H, m), 8.0-8.2 (1H, m).

Production Example 30 Production of(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol

A light yellow oil product,2-(2-(1-benzothiophene-5-yl)ethoxy)-1-((3S)-3-hydroxy-1-pyrrolidinol))-1-ethanonewas obtained in the same manner as in Production Example 16(1).

Subsequently, a light yellow oil product,(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol wasobtained in the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3386, 2936, 2867, 1438, 1111, 755, 702.

NMR (CDCl₃) δppm: 1.5-2.0 (1H, m), 2.0-3.0 (5H, m), 2.66 (2H, t, J=6Hz), 3.00 (2H, t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 7.21 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H,d, J=5 Hz), 7.67 (1H, s), 7.79 (1H, d, J=8 Hz).

Production Example 31 Production of(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal,(3S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol oxalatewas obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3366, 2941, 2867, 2686, 1718, 1701, 1404, 1114, 720.

NMR (DMSO-d₆) δppm: 1.5-2.2 (2H, m), 2.8-3.5 (8H, m), 3.70 (4H, t, J=6Hz), 4.2-4.5 (1H, m), 7.28 (1H, d, J=8 Hz), 7.40 (1H, d, J=5 Hz), 7.73(1H, d, J=5 Hz), 7.76 (1H, s), 7.91 (1H, d, J=8 Hz).

Production Example 32 Production of(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol

An achromatic crystal,2-(2-(1-benzothiophene-5-yl)ethoxy)-1-((3R)-3-hydroxy-1-pyrrolidinyl))-1-ethanonewas obtained in the same manner as in Production Example 16(1).

IR (KBr)cm⁻¹: 3408, 2937, 1637, 1137, 1108, 812, 703.

Subsequently, a light yellow oil product,(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol wasobtained in the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3373, 2940, 1438, 1111, 755, 702.

NMR (CDCl₃) δppm: 1.5-2.0 (1H, m), 2.0-3.0 (5H, m), 2.68 (2H, t, J=6Hz), 3.01 (2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 7.21 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H,d, J=5 Hz), 7.67 (1H, s), 7.79 (1H, d, J=8 Hz).

Production Example 33 Production of(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal,(3R)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinol oxalatewas obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3318, 2870, 1718, 1114, 720.

NMR (DMSO-d₆) δppm: 1.5-2.2 (2H, m), 2.8-3.5 (8H, m), 3.70 (4H, t, J=6Hz), 4.2-4.5 (1H, m), 7.28 (1H, d, J=8 Hz), 7.40 (1H, d, J=5 Hz), 7.73(1H, d, J=5 Hz), 7.76 (1H, s), 7.91 (1H, d, J=8 Hz).

Production Example 34 Production of(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol

An achromatic oil product,2-(2-(1-benzothiophene-6-yl)ethoxy)-1-((3S)-3-hydroxy-1-pyrrolidinyl))-1-ethanonewas obtained in the same manner as in Production Example 16(1).

IR (neat)cm⁻¹: 3385, 2944, 1637, 1133, 820, 699.

Subsequently, an achromatic oil product,(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol wasobtained in the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3385, 2940, 2867, 1110, 820, 757.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.32 (1H, dt, J=6, 9Hz), 2.54 (1H, dd, J=5, 10 Hz), 2.6-2.7 (3H, m), 2.85 (1H, dt, J=5, 9Hz), 3.01 (2H, t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz),4.2-4.3 (1H, m), 7.23 (1H, d, J=8 Hz), 7.29 (1H, d, J=5 Hz), 7.37 (1H,d, J=5 Hz), 7.73 (1H, d, J=8 Hz), 7.74 (1H, s).

Production Example 35 Production of(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal,(3S)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol oxalatewas obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3364, 2938, 2692, 1718, 1400, 1201, 1114, 720.

NMR (DMSO-d₆) δppm: 1.7-1.8 (1H, m), 1.9-2.1 (1H, m), 2.96 (2H, t, J=7Hz), 3.0-3.1 (1H, m), 3.1-3.3 (5H, m), 3.70 (4H, t, J=7 Hz), 4.2-4.3(1H, m), 7.29 (1H, d, J=8 Hz), 7.41 (1H, d, J=5 Hz), 7.68 (1H, d, J=5Hz), 7.80 (1H, d, J=8 Hz), 7.87 (1H, s).

Production Example 36 Production of(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol

An oil product,2-(2-(1-benzothiophene-6-yl)ethoxy)-1-((3R)-3-hydroxy-1-pyrrolidinyl))-1-ethanonewas obtained in the same manner as in Production Example 16(1).

IR (neat)cm⁻¹: 3386, 2940, 1637, 1107, 820, 758.

Subsequently, an achromatic oil product,(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol wasobtained in the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3385, 2940, 2867, 1110, 820, 757.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.32 (1H, dt, J=6, 9Hz), 2.54 (1H, dd, J=5, 10 Hz), 2.6-2.7 (3H, m), 2.85 (1H, dt, J=5, 9Hz), 3.01 (2H, t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz),4.2-4.3 (1H, m), 7.23 (1H, d, J=8 Hz), 7.29 (1H, d, J=5 Hz), 7.37 (1H,d, J=5 Hz), 7.73 (1H, d, J=8 Hz), 7.74 (1H, s).

Production Example 37 Production of(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal,(3R)-1-(2-(2-(1-benzothiophene-6-yl)ethoxy)ethyl)-3-pyrrolidinol oxalatewas obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3364, 2938, 2688, 1718, 1400, 1201, 1114, 720.

NMR (DMSO-d₆) δppm: 1.7-1.8 (1H, m), 1.9-2.1 (1H, m), 2.96 (2H, t, J=7Hz), 3.0-3.1 (1H, m), 3.1-3.3 (5H, m), 3.70 (4H, t, J=7 Hz), 4.2-4.3(1H, m), 7.29 (1H, d, J=8 Hz), 7.41 (1H, d, J=5 Hz), 7.68 (1H, d, J=5Hz), 7.80 (1H, d, J=8 Hz), 7.87 (1H, s).

Production Example 38 Production of(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol

2-(2-(1-benzothiophene-3-yl)ethoxy)-1-((3R)-3-hydroxy-1-pyrrolidinyl))-1-ethanonewas obtained in the same manner as in Production Example 16(1).

NMR (CDCl₃) δppm: 1.8-1.9 (1H, m), 1.9-2.0 (1H, m), 3.1-3.4 (3H, m),3.3-3.7 (3H, m), 3.8-4.0 (2H, m), 4.0-4.2 (2H, m), 4.3-4.5 (1H, m), 7.27(1/2H, s), 7.28 (1/2H, s), 7.3-7.5 (2H, m), 7.7-7.8 (1H, m), 7.8-7.9(1H, m).

Subsequently, a yellow oil product,(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol wasobtained in the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3386, 2942, 1458, 1429, 1113, 759, 733.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.34 (1H, dt, J=6, 9Hz), 2.55 (1H, dd, J=5, 10 Hz), 2.6-2.8 (3H, m), 2.85 (1H, dt, J=5, 9Hz), 3.14 (2H, t, J=7 Hz), 3.61 (2H, t, J=6 Hz), 3.80 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 7.21 (1H, s), 7.34 (1H, dt, J=1, 7 Hz), 7.38 (1H, dt,J=1, 7 Hz), 7.76 (1H, dd, J=1, 7 Hz), 7.85 (1H, dd, J=1, 7 Hz).

Production Example 39 Production of(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride

0.99 g of(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinol wasdissolved in 5.0 ml of ethyl acetate. Thereafter, 1.10 ml of an ethylacetate solution containing 3.25 mol/l dry hydrogen chloride was addedto the obtained solution, and the obtained mixture was then stirred at aroom temperature for 1 hour. Thereafter, the solvent was distilled awayunder a reduced pressure, so as to obtain 1.05 g of a light yellow oilproduct,(3R)-1-(2-(2-(1-benzothiophene-3-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride.

IR (neat)cm⁻¹: 3368, 2946, 1560, 1430, 1121, 765, 734.

NMR (CDCl₃) δppm: 1.9-2.1 (1H, m), 2.1-2.3 (1H, m), 2.8-3.0 (2H, m),3.1-3.2 (4H, m), 3.29 (1H, d, J=12 Hz), 3.3-3.5 (1H, m), 3.8-3.9 (4H,m), 4.3-4.4 (1H, m), 7.24 (1H, s), 7.35 (1H, t, J=8 Hz), 7.40 (1H, t,J=8 Hz), 7.76 (1H, d, J=8 Hz), 7.86 (1H, d, J=8 Hz).

Production Example 40 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol

An oil product,2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(4-hydroxy-1-piperidinyl)-1-ethanonewas obtained in the same manner as in Production Example 16(1).

Subsequently, a yellow oil product,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol was obtainedin the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3386, 2939, 1110, 1071, 754, 701.

NMR (CDCl₃) δppm: 1.5-2.3 (6H, m), 2.5-3.0 (2H, m), 2.56 (2H, t, J=6Hz), 3.00 (2H, t, J=7 Hz), 3.5-3.9 (1H, m), 3.58 (2H, t, J=6 Hz), 3.70(2H, t, J=7 Hz), 7.19 (1H, d, J=8 Hz), 7.27 (1H, d, J=5 Hz), 7.41 (1H,d, J=5 Hz), 7.65 (1H, s), 7.78 (1H, d, J=8 Hz).

Production Example 41 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol hydrochloride

A light brown crystal,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-4-piperidinol hydrochloridewas obtained in the same manner as in Production Example 21.

IR (KBr)cm⁻¹: 3312, 2946, 2691, 1457, 1124, 1043, 769, 712.

NMR (CDCl₃) δppm: 1.5-2.5 (4H, m), 2.8-3.2 (6H, m), 2.99 (2H, t, J=6Hz), 3.76 (2H, t, J=6 Hz), 3.8-4.2 (3H, m), 7.19 (1H, d, J=8 Hz), 7.30(1H, d, J=5 Hz), 7.44 (1H, d, J=5 Hz), 7.67 (1H, s), 7.80 (1H, d, J=8Hz).

Production Example 42 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol

A yellow oil product,2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-piperidinyl)-1-ethanonewas obtained in the same manner as in Production Example 16(1).

IR (neat)cm⁻¹: 3408, 2938, 1637, 1114, 704.

Subsequently, a yellow oil product,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol was obtainedin the same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3387, 2937, 1438, 1109, 703.

NMR (CDCl₃) δppm: 1.4-2.0 (4H, m), 2.0-2.7 (6H, m), 2.57 (2H, t, J=6Hz), 3.00 (2H, t, J=7 Hz), 3.56 (2H, t, J=6 Hz), 3.6-3.9 (1H, m), 3.70(2H, t, J=7 Hz), 7.20 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H,d, J=5 Hz), 7.66 (1H, s), 7.79 (1H, d, J=8 Hz).

Production Example 43 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol hydrochloride

An achromatic crystal,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-piperidinol hydrochloridewas obtained in the same manner as in Production Example 21.

IR (KBr)cm⁻¹: 3260, 2949, 2638, 1433, 1129, 1045, 702, 668.

NMR (CDCl₃) δppm: 1.5-2.0 (4H, m), 2.1-2.8 (2H, m), 2.99 (2H, t, J=6Hz), 3.1-3.6 (4H, m), 3.76 (2H, t, J=6 Hz), 3.8-4.1 (3H, m), 7.20 (1H,d, J=8 Hz), 7.30 (1H, d, J=5 Hz), 7.44 (1H, d, J=5 Hz), 7.67 (1H, s),7.80 (1H, d, J=8 Hz).

Production Example 44 Production of1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol

2-(2-(1-benzofuran-5-yl)ethoxy)-1-(4-hydroxy-1-piperidinyl)-1-ethanonewas obtained in the same manner as in Production Example 16(1).

IR (neat)cm⁻¹: 3406, 2931, 1636, 1110, 771, 740.

Subsequently, an achromatic oil product,1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol was obtained inthe same manner as in Production Example 16(2).

IR (neat)cm⁻¹: 3359, 2939, 1468, 1111, 1073, 882, 768, 739.

NMR (CDCl₃) δppm: 1.5-2.3 (6H, m), 2.5-3.0 (2H, m), 2.57 (2H, t, J=6Hz), 2.97 (2H, t, J=7 Hz), 3.5-3.8 (1H, m), 3.58 (2H, t, J=6 Hz), 3.68(2H, t, J=7 Hz), 6.71 (1H, dd, J=1, 2 Hz), 7.13 (1H, dd, J=2, 8 Hz),7.40 (1H, d, J=8 Hz), 7.42 (1H, dd, J=1, 2 Hz), 7.55 (1H, d, J=2 Hz).

Production Example 45 Production of1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol hydrochloride

A light yellow oil product,1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-4-piperidinol hydrochloride wasobtained in the same manner as in Production Example 39.

IR (neat)cm⁻¹: 3366, 2938, 2638, 1458, 1126, 776, 742.

NMR (CDCl₃) δppm: 1.6-2.4 (4H, m), 2.8-3.2 (8H, m), 3.71 (2H, t, J=6Hz), 3.7-4.1 (3H, m), 6.72 (1H, dd, J=1, 2 Hz), 7.12 (1H, dd, J=2, 8Hz), 7.44 (1H, d, J=8 Hz), 7.42 (1H, dd, J=1, 2 Hz), 7.60 (1H, d, J=2Hz).

Production Example 46 Production of1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol

(1) 1.28 g of 2-(2-(1-benzofuran-5-yl)ethoxy)acetic acid was dissolvedin 13.0 ml of tetrahydrofuran. The obtained solution was cooled to 5° C.Thereafter, 1.41 g of 1,1′-carbonyldiimidazole was added thereto, andthe obtained mixture was then stirred at a room temperature for 2 hours.Thereafter, 1.22 ml of triethylamine and 0.72 ml of 3-pyrrolidinol wereadded to the reaction mixture, followed by stirring at a roomtemperature for 2 hours. Thereafter, water and ethyl acetate were addedto the reaction mixture. The pH of the obtained mixture was adjusted topH 1 by addition of 6 mol/l hydrochloric acid, and an organic layer wasthen separated. The organic layer was successively washed with asaturated sodium bicarbonate solution and a saturated saline solution,and then dried over anhydrous magnesium sulfate. Subsequently, thesolvent was distilled away under a reduced pressure, so as to obtain1.39 g of an achromatic oil product,2-(2-(1-benzofuran-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone.

IR (neat)cm⁻¹: 3398, 2943, 1637, 1467, 1128, 1030, 771, 741.

(2) 1.39 g of2-(2-(1-benzofuran-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas dissolved in 14.0 ml of tetrahydrofuran. Thereafter, 14.4 ml of atetrahydrofuran solution containing a 1 mol/l borane-tetrahydrofurancomplex was added dropwise to the obtained solution while cooling onice, and the obtained mixture was then stirred at a room temperature for17 hours. Thereafter, 8.0 ml of 6 mol/l hydrochloric acid was added tothe reaction mixture, and the obtained mixture was heated to reflux for1 hour. After cooling, water and ethyl acetate were added to thereaction mixture. The pH of the obtained mixture was adjusted to pH 10by addition of a 2 mol/l aqueous sodium hydroxide solution, and anorganic layer was separated. The organic layer was successively washedwith water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. Thereafter, the solvent was distilled awayunder a reduced pressure. The residue was purified by columnchromatography (eluent; chloroform:methanol=30:1 to 10:1), so as toobtain 0.96 g of an achromatic oil product,1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol.

IR (neat)cm⁻¹: 3386, 2941, 1468, 1261, 1110, 1030, 882, 769, 738.

NMR (CDCl₃) δppm: 1.5-2.0 (1H, m), 1.9-3.0 (5H, m), 2.68 (2H, t, J=6Hz), 2.98 (2H, t, J=7 Hz), 3.58 (2H, t, J=6 Hz), 3.70 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 6.71 (1H, dd, J=1, 2 Hz), 7.14 (1H, d, J=8 Hz), 7.42(1H, d, J=8 Hz), 7.4-7.5 (1H, m), 7.59 (1H, d, J=2 Hz).

Production Example 47 Production of1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-piperidinol oxalate

An achromatic crystal,1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-piperidinol oxalate wasobtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3418, 2945, 2698, 1715, 1197, 1111, 720.

NMR (DMSO-d₆) δppm: 1.6-2.3 (2H, m), 2.92 (2H, t, J=7 Hz), 3.0-3.5 (6H,m), 3.5-3.8 (4H, m), 4.2-4.5 (1H, m), 6.89 (1H, dd, J=1, 2 Hz), 7.19(1H, dd, J=1, 8 Hz), 7.50 (1H, d, J=8 Hz), 7.5-7.6 (1H, m), 7.94 (1H, d,J=2 Hz).

Production Example 48 Production of(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediol

A yellow oil product,2-(2-(1-benzothiophene-5-yl)ethoxy)-1-((3R*,4R*)-3,4-dihydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Production Example 46(1).

IR (neat)cm⁻¹: 3370, 2935, 2874, 1636, 1131, 756, 701.

Subsequently, a yellow oil product,(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediolwas obtained in Production Example 46(2).

IR (neat)cm⁻¹: 3386, 2938, 2866, 1438, 1113, 756, 703.

NMR (CDCl₃) δppm: 2.5-3.0 (5H, m), 3.00 (2H, t, J=7 Hz), 3.2-3.7 (1H,m), 3.56 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 3.9-4.4 (2H, m), 7.20(1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.43 (1H, d, J=5 Hz), 7.66 (1H,s), 7.80 (1H, d, J=8 Hz).

Production Example 49 Production of(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinedioloxalate

An achromatic crystal,(3R*,4R*)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinedioloxalate was obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3309, 2929, 1718, 1617, 1199, 1104, 702.

NMR (DMSO-d₆) δppm: 2.8-3.2 (6H, m), 3.2-3.8 (6H, m), 4.1-4.4 (2H, m),7.26 (1H, d, J=8 Hz), 7.39 (1H, d, J=5 Hz), 7.72 (1H, d, J=5 Hz), 7.75(1H, s), 7.90 (1H, d, J=8 Hz).

Production Example 50 Production of1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-pyrrolidinol

An achromatic oil product,2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Production Example 46(1).

IR (neat)cm⁻¹: 3394, 2941, 1637, 1465, 1197, 1131, 1015, 841, 759.

Subsequently, an achromatic oil product,1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-pyrrolidinol wasobtained in Production Example 46(2).

IR (neat)cm⁻¹: 3386, 2940, 1466, 1430, 1198, 1131, 1015, 837, 762.

NMR (CDCl₃) δppm: 1.5-2.4 (3H, m), 2.5-3.0 (5H, m), 2.99 (2H, t, J=7Hz), 3.59 (2H, t, J=6 Hz), 3.67 (2H, t, J=7 Hz), 3.85 (3H, s), 4.2-4.4(1H, m), 6.68 (1H, d, J=2 Hz), 6.99 (1H, s), 7.34 (1H, s), 7.54 (1H, d,J=2 Hz).

Production Example 51 Production of1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-piperidinol oxalate

An achromatic crystal,1-(2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)ethyl)-3-piperidinol oxalatewas obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3396, 2942, 2691, 1718, 1636, 1465, 1198, 1130, 720.

NMR (DMSO-d₆) δppm: 1.7-2.3 (2H, m), 2.8-3.6 (6H, m), 2.91 (2H, t, J=6Hz), 3.5-3.9 (4H, m), 3.83 (3H, s), 4.2-4.5 (1H, m), 6.86 (1H, d, J=2Hz), 7.17 (1H, s), 7.43 (1H, s), 7.88 (1H, d, J=2 Hz).

Production Example 52 Production of1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol

An achromatic oil product,2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanonewas obtained in the same manner as in Production Example 46(1).

IR (neat)cm⁻¹: 3381, 2944, 1638, 1475, 1201, 1125, 1011, 758.

Subsequently, an achromatic oil product,1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinol wasobtained in Production Example 46(2).

IR (neat)cm⁻¹: 3398, 2938, 1475, 1202, 1094, 757, 730.

NMR (CDCl₃) δppm: 1.5-2.4 (3H, m), 2.5-3.0 (5H, m), 2.98 (2H, t, J=7Hz), 3.59 (2H, t, J=6 Hz), 3.68 (2H, t, J=7 Hz), 3.86 (3H, s), 4.2-4.4(1H, m), 6.65 (1H, d, J=2 Hz), 7.00 (1H, s), 7.35 (1H, s), 7.50 (1H, d,J=2 Hz).

Production Example 53 Production of1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride

An achromatic oil product,1-(2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinolhydrochloride was obtained in the same manner as in Production Example39.

IR (neat)cm⁻¹: 3377, 2938, 2694, 1475, 1202, 1124, 1093, 1011.

NMR (CDCl₃) δppm: 1.7-2.2 (2H, m), 2.8-3.6 (6H, m), 2.96 (2H, t, J=6Hz), 3.5-4.2 (4H, m), 3.86 (3H, s), 4.3-4.6 (1H, m), 6.6-6.7 (1H, m),7.01 (1H, s), 7.34 (1H, d, J=1 Hz), 7.51 (1H, d, J=2 Hz).

Production Example 54 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine

(1) 1.00 g of 2-(2-(1-benzothiophene-5-yl)ethoxy)acetic acid wasdissolved in 10.0 ml of tetrahydrofuran. The obtained solution wascooled to 5° C. Thereafter, 1.03 g of 1,1′-carbonyldiimidazole was addedthereto, and the obtained mixture was then stirred at a room temperaturefor 1 hour. The reaction solution was cooled to 5° C. Thereafter, 0.88ml of triethylamine and 1.18 g of tert-butyl=3-pyrrolidinyl carbamatewere added to the reaction mixture, followed by stirring at a roomtemperature for 1 hour. Thereafter, water and ethyl acetate were addedto the reaction mixture. The pH of the obtained mixture was adjusted topH 4 by addition of 6 mol/l hydrochloric acid, and an organic layer wasthen separated. The organic layer was successively washed with asaturated sodium bicarbonate solution and a saturated saline solution,and then dried over anhydrous magnesium sulfate. Subsequently, thesolvent was distilled away under a reduced pressure, so as to obtain2.00 g of a light yellow oil product,tert-butyl=1-(2-(2-(1-benzothiophene-5-yl)ethoxy)acetyl)-3-pyrrolidinylcarbamate.(2) 2.00 g of the obtainedtert-butyl=1-(2-(2-(1-benzothiophene-5-yl)ethoxy)acetyl)-3-pyrrolidinylcarbamate was dissolved in 2.0 ml of tetrahydrofuran. The obtainedsolution was cooled to 5° C. Thereafter, 10.6 ml of a tetrahydrofuransolution containing a 1 mol/l borane-tetrahydrofuran complex was addeddropwise to the obtained solution, and the obtained mixture was thenstirred at a room temperature for 17 hours. Thereafter, 3.5 ml of 6mol/l hydrochloric acid was added to the reaction mixture, and theobtained mixture was heated to reflux for 3 hours. After the reactionmixture was cooled, water and ethyl acetate were added thereto. The pHof the obtained mixture was adjusted to pH 10 by addition of a 5 mol/laqueous sodium hydroxide solution, and an organic layer was separated.The organic layer was washed with a saturated saline solution and thendried over anhydrous magnesium sulfate. Thereafter, the solvent wasdistilled away under a reduced pressure. The residue was purified bycolumn chromatography (eluent; chloroform:methanol=30:1 to 15:1), so asto obtain 1.01 g of a light yellow oil product,1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine.

IR (neat)cm⁻¹: 3358, 2938, 2861, 1438, 1112, 1052, 755, 703.

NMR (CDCl₃) δppm: 1.2-1.7 (1H, m), 1.9-3.0 (7H, m), 2.01 (2H, s), 3.00(2H, t, J=7 Hz), 3.3-3.7 (1H, m), 3.57 (2H, t, J=6 Hz), 3.71 (2H, t, J=7Hz), 7.20 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.41 (1H, d, J=5 Hz),7.66 (1H, s), 7.78 (1H, d, J=8 Hz).

Production Example 55 Production of1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinamine dioxalate

0.71 g of 1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinaminewas dissolved in 3.0 ml of ethyl acetate. Thereafter, 4.0 ml of an ethylacetate solution containing 0.44 g of oxalic acid was added to theobtained solution, and the obtained mixture was stirred at a roomtemperature for 1 hour and then at 5° C. for 1 hour. Thereafter,precipitated crystals were collected by filtration, washed with ethylacetate, and then dried, so as to obtain 1.03 g of an achromaticcrystal, 1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-pyrrolidinaminedioxalate.

IR (KBr)cm⁻¹: 3447, 2938, 1406, 1279, 1115, 720.

NMR (DMSO-d₆) δppm: 1.7-2.5 (2H, m), 2.8-3.5 (8H, m), 3.5-4.0 (5H, m),7.27 (1H, d, J=8 Hz), 7.40 (1H, d, J=5 Hz), 7.72 (1H, d, J=5 Hz), 7.75(1H, s), 7.90 (1H, d, J=8 Hz).

Production Example 56 Production of1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine

In the same manner as in Production Example 54(1),tert-butyl=1-(2-(2-(1-benzofuran-5-yl)ethoxy)acetyl)-3-pyrrolidinylcarbamate was obtained.

Subsequently, a yellow oil product,1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine was obtainedin the same manner as in Production Example 54(2).

IR (neat)cm⁻¹: 3356, 2938, 1467, 1261, 1111, 1030, 882, 769, 740.

NMR (CDCl₃) δppm: 1.2-1.7 (1H, m), 2.02 (2H, s), 2.1-3.0 (7H, m), 2.98(2H, t, J=7 Hz), 3.3-3.7 (1H, m), 3.57 (2H, t, J=6 Hz), 3.69 (2H, t, J=7Hz), 6.71 (1H, dd, J=1, 2 Hz), 7.15 (1H, dd, J=1, 7 Hz), 7.40 (1H, d,J=7 Hz), 7.4-7.5 (1H, m), 7.59 (1H, d, J=2 Hz).

Production Example 57 Production of1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine oxalate

An achromatic crystal,1-(2-(2-(1-benzofuran-5-yl)ethoxy)ethyl)-3-pyrrolidinamine oxalate wasobtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3408, 2952, 1615, 1311, 1127, 769.

NMR (DMSO-d₆) δppm: 1.5-1.9 (1H, m), 1.8-2.4 (1H, m), 2.1-3.0 (6H, m),2.89 (2H, t, J=7 Hz), 3.4-3.8 (5H, m), 6.89 (1H, dd, J=1, 2 Hz), 7.18(1H, d, J=8 Hz), 7.50 (1H, d, J=8 Hz), 7.4-7.6 (1H, m), 7.94 (1H, d, J=2Hz).

Production Example 58 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol

1.20 g of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in12 ml of N,N-dimethylformamide. Thereafter, 0.82 g of 3-pyrrolidinol and1.30 g of potassium carbonate were added to the obtained solution, andthe mixture was then stirred at 85° C. for 2.5 hours. After the reactionmixture was cooled, water and ethyl acetate were added thereto, and anorganic layer was separated. The organic layer was successively washedwith water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. Thereafter, the solvent was distilled awayunder a reduced pressure. The residue was purified by columnchromatography (eluent; chloroform:methanol=20:1 to 10:1), so as toobtain 0.78 g of an achromatic oil product,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol.

IR (neat)cm⁻¹: 3386, 2943, 1438, 1106, 1052, 755, 701.

NMR (CDCl₃) δppm: 1.5-2.0 (3H, m), 2.0-3.0 (7H, m), 2.98 (2H, t, J=7Hz), 3.49 (2H, t, J=6 Hz), 3.67 (2H, t, J=7 Hz), 4.2-4.4 (1H, m),7.1-7.3 (2H, m), 7.41 (1H, d, J=6 Hz), 7.66 (1H, s), 7.78 (1H, d, J=8Hz).

Production Example 59 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinolhydrochloride

An achromatic crystal,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinolhydrochloride was obtained in the same manner as in Production Example21.

IR (KBr)cm⁻¹: 3368, 2937, 2695, 1438, 1108, 821, 764, 708.

NMR (CDCl₃) δppm: 1.8-2.3 (4H, m), 2.3-3.6 (6H, m), 2.96 (2H, t, J=6Hz), 3.50 (2H, t, J=6 Hz), 3.68 (2H, t, J=7 Hz), 4.3-4.7 (1H, m), 7.21(1H, d, J=8 Hz), 7.30 (1H, d, J=5 Hz), 7.43 (1H, d, J=5 Hz), 7.67 (1H,s), 7.80 (1H, d, J=8 Hz).

Production Example 60 Production of1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol

A light yellow oil product,1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol was obtained inthe same manner as in Production Example 58.

IR (neat)cm⁻¹: 3386, 2942, 1467, 1261, 1108, 1030, 883, 740.

NMR (CDCl₃) δppm: 1.5-2.0 (3H, m), 2.0-3.0 (7H, m), 2.95 (2H, t, J=7Hz), 3.49 (2H, t, J=6 Hz), 3.65 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 6.71(1H, dd, J=1, 2 Hz), 7.14 (1H, dd, J=1, 8 Hz), 7.3-7.5 (2H, m), 7.58(1H, d, J=2 Hz).

Production Example 61 Production of1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol hydrochloride

A light yellow oil product,1-(3-(2-(1-benzofuran-5-yl)ethoxy)propyl)-3-pyrrolidinol hydrochloridewas obtained in the same manner as in Production Example 39.

IR (neat)cm⁻¹: 3339, 2941, 2605, 1468, 1262, 1110, 773, 742.

NMR (CDCl₃) δppm: 1.6-2.4 (4H, m), 2.4-4.0 (12H, m), 4.4-4.8 (1H, m),6.72 (1H, d, J=2 Hz), 7.12 (1H, d, J=8 Hz), 7.3-7.6 (2H, m), 7.59 (1H,d, J=2 Hz).

Production Example 62 Production of1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinol

A yellow oil product,1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinolwas obtained in the same manner as in Production Example 58.

IR (neat)cm⁻¹: 3422, 2952, 1458, 1257, 1106, 838, 747, 711.

NMR (CDCl₃) δppm: 1.5-3.0 (10H, m), 3.00 (2H, t, J=7 Hz), 3.4-3.6 (2H,m), 3.68 (2H, t, J=7 Hz), 4.2-4.4 (1H, m), 7.23 (1H, d, J=5 Hz), 7.36(1H, d, J=5 Hz), 7.51 (1H, d, J=10 Hz), 7.66 (1H, d, J=7 Hz).

Production Example 63 Production of1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinolhydrochloride

A yellow oil product,1-(3-(2-(6-fluoro-1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinolhydrochloride was obtained in the same manner as in Production Example39.

IR (neat)cm⁻¹: 3377, 2954, 2702, 1458, 1257, 1107, 750, 712.

NMR (CDCl₃) δppm: 1.8-2.3 (4H, m), 2.8-3.6 (8H, m), 3.53 (2H, t, J=6Hz), 3.69 (2H, t, J=7 Hz), 4.3-4.4 (1H, m), 7.27 (1H, d, J=5 Hz), 7.39(1H, d, J=5 Hz), 7.52 (1H, d, J=10 Hz), 7.67 (1H, d, J=7 Hz).

Production Example 64 Production of(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediol

An achromatic oil product,(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediolwas obtained in the same manner as in Production Example 58.

IR (neat)cm⁻¹: 3387, 2940, 1438, 1159, 1108, 1051, 703.

NMR (CDCl₃) δppm: 1.5-1.9 (2H, m), 2.4-2.8 (6H, m), 2.98 (2H, t, J=7Hz), 3.47 (2H, t, J=6 Hz), 3.67 (2H, t, J=7 Hz), 4.1-4.3 (2H, m), 7.20(1H, dd, J=1, 8 Hz), 7.27 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.65(1H, d, J=1 Hz), 7.79 (1H, d, J=8 Hz).

Production Example 65 Production of(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediolhydrochloride

An achromatic crystal,(3R,4S)-1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3,4-pyrrolidinediolhydrochloride was obtained in the same manner as in Production Example21.

IR (KBr)cm⁻¹: 3381, 2871, 2602, 1120, 808, 768, 718.

NMR (DMSO-d₆) δppm: 1.8-2.0 (2H, m), 2.8-3.8 (12H, m), 3.9-4.3 (2H, m),7.25 (1H, dd, J=2, 8 Hz), 7.39 (1H, d, J=5 Hz), 7.72 (1H, d, J=5 Hz),7.73 (1H, d, J=2 Hz), 7.90 (1H, d, J=8 Hz).

Production Example 66 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol

A light yellow oil product,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol was obtainedin the same manner as in Production Example 58.

IR (neat)cm⁻¹: 3385, 2935, 1438, 1364, 1111, 755, 701.

NMR (CDCl₃) δppm: 1.4-2.2 (8H, m), 2.1-2.5 (2H, m), 2.5-3.0 (2H, m),2.98 (2H, t, J=7 Hz), 3.48 (2H, t, J=6 Hz), 3.5-3.8 (1H, m), 3.67 (2H,t, J=7 Hz), 7.1-7.3 (2H, m), 7.42 (1H, d, J=5 Hz), 7.66 (1H, s), 7.79(1H, d, J=8 Hz).

Production Example 67 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol oxalate

An achromatic crystal,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-4-piperidinol oxalate wasobtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3420, 2866, 1718, 1616, 1190, 1120, 705.

NMR (DMSO-d₆) δppm: 1.5-2.0 (6H, m), 2.8-3.1 (8H, m), 3.4-3.8 (1H, m),3.44 (2H, t, J=6 Hz), 3.64 (2H, t, J=6 Hz), 7.24 (1H, d, J=8 Hz), 7.40(1H, d, J=5 Hz), 7.6-7.8 (2H, m), 7.91 (1H, d, J=8 Hz).

Production Example 68 Production of1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinol

0.80 g of 2-(2-(2-naphthyl)ethoxy)ethyl)=methanesulfonate was dissolvedin 8 ml of N,N-dimethylformamide. Thereafter, 0.45 ml of 3-pyrrolidinoland 0.75 g of potassium carbonate were added to the obtained solution,and the mixture was stirred at 90° C. for 2 hours. After the reactionmixture was cooled, water and ethyl acetate were added, and an organiclayer was separated. The organic layer was successively washed withwater and a saturated saline solution, and then dried over anhydrousmagnesium sulfate. Thereafter, the solvent was distilled away under areduced pressure. The residue was purified by column chromatography(eluent; chloroform:methanol=8:1 to 5:1), so as to obtain 0.51 g of anachromatic oil product,1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinol.

IR (neat)cm⁻¹: 3422, 2938, 1112, 820, 749.

NMR (CDCl₃) δppm: 1.5-1.9 (1H, m), 2.0-2.5 (3H, m), 2.5-3.0 (4H, m),3.05 (2H, t, J=7 Hz), 3.59 (2H, t, J=6 Hz), 3.75 (2H, t, J=7 Hz),4.2-4.4 (1H, m), 7.2-7.6 (4H, m), 7.6-8.0 (3H, m).

Production Example 69 Production of1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinol oxalate

An achromatic crystal, 1-(2-(2-(2-naphthyl)ethoxy)ethyl)-3-pyrrolidinoloxalate was obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3366, 2945, 1405, 1113, 820, 720.

NMR (DMSO-d₆) δppm: 1.6-2.3 (2H, m), 2.7-3.5 (8H, m), 3.5-3.9 (4H, m),4.2-4.5 (1H, m), 7.4-7.6 (3H, m), 7.7-8.0 (4H, m).

Production Example 70 Production of(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediol

2.50 g of 2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)=methanesulfonate wasdissolved in 25 ml of N,N-dimethylformamide. Thereafter, 1.40 g of(3R,4S)-3,4-pyrrolidinediol hydrochloride and 4.70 ml of triethylaminewere added to the obtained solution, and the mixture was then stirred at90° C. for 1 hour. After cooling, water and ethyl acetate were added tothe reaction mixture. The pH of the obtained mixture was adjusted to pH10 by addition of a 2 mol/l aqueous sodium hydroxide solution, and anorganic layer was then separated. The organic layer was successivelywashed with water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. The solvent was then distilled away under areduced pressure. The residue was purified by column chromatography(eluent; chloroform:methanol=8:1 to 5:1), so as to obtain 0.84 g of ayellow oil product,(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediol.

IR (neat)cm⁻¹: 3390, 2940, 1438, 1111, 1050, 703.

NMR (CDCl₃) δppm: 2.5-3.0 (6H, m), 3.00 (2H, t, J=7 Hz), 3.55 (2H, t,J=6 Hz), 3.70 (2H, t, J=7 Hz), 4.0-4.3 (2H, m), 7.21 (1H, dd, J=1, 8Hz), 7.28 (1H, d, J=5 Hz), 7.43 (1H, d, J=5 Hz), 7.66 (1H, d, J=1 Hz),7.80 (1H, d, J=8 Hz).

Production Example 71 Production of(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediolhydrochloride

An achromatic crystal,(3R,4S)-1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3,4-pyrrolidinediolhydrochloride was obtained in the same manner as in Production Example21.

IR (KBr)cm⁻¹: 3194, 2854, 1365, 1348, 1130, 1111, 820, 712.

NMR (DMSO-d₆) δppm: 2.8-4.0 (12H, m), 3.9-4.3 (2H, m), 7.2-7.5 (2H, m),7.7-8.2 (3H, m).

Production Example 72 Production oftert-butyl=1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinylcarbamate

0.70 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)propyl=methanesulfonate wasdissolved in 7 ml of N,N-dimethylformamide. Thereafter, 1.03 g oftert-butyl=3-pyrrolidinyl carbamate carbonate and 1.86 ml oftriethylamine were added to the obtained solution, and the mixture wasthen stirred at 90° C. for 2 hours. After cooling, water and ethylacetate were added to the reaction mixture. The pH of the obtainedmixture was adjusted to pH 10 by addition of 6 mol/l hydrochloric acid,and an organic layer was then separated. The organic layer wassuccessively washed with water and a saturated saline solution, and thendried over anhydrous magnesium sulfate. Thereafter, the solvent was thendistilled away under a reduced pressure, so as to obtain 1.12 g of ayellow oil product,tert-butyl=1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinylcarbamate.

NMR (CDCl₃) δppm: 1.2-1.9 (3H, m), 1.44 (9H, s), 1.9-3.0 (7H, m), 2.99(2H, t, J=7 Hz), 3.49 (2H, t, J=6 Hz), 3.67 (2H, t, J=7 Hz), 4.0-4.3(1H, m), 7.19 (1H, d, J=8 Hz), 7.27 (1H, d, J=5 Hz), 7.42 (1H, d, J=5Hz), 7.66 (1H, s), 7.79 (1H, d, J=8 Hz).

Production Example 73 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine

1.12 g oftert-butyl=1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinylcarbamate was dissolved in 7.0 ml of ethyl acetate. Thereafter, 1.86 mlof 6 mol/l hydrochloric acid was added to the obtained solution, and themixture was then heated to reflux for 1 hour. After cooling, water andethyl acetate were added to the reaction mixture. The pH of the obtainedmixture was adjusted to pH 10 by addition of a 2 mol/l aqueous sodiumhydroxide solution, and an organic layer was then separated. The organiclayer was successively washed with water and a saturated salinesolution, and then dried over anhydrous magnesium sulfate. The solventwas then distilled away under a reduced pressure. The residue waspurified by column chromatography (eluent; chloroform:methanol=30:1 to20:1), so as to obtain 0.38 g of a light yellow oil product,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine.

IR (neat)cm⁻¹: 3357, 2937, 2861, 2796, 1146, 1108, 755, 701.

NMR (CDCl₃) δppm: 1.2-1.9 (4H, m), 1.9-2.8 (7H, m), 2.97 (2H, t, J=7Hz), 3.48 (2H, t, J=6 Hz), 3.66 (2H, t, J=7 Hz), 7.19 (1H, d, J=8 Hz),7.23 (1H, d, J=5 Hz), 7.39 (1H, d, J=5 Hz), 7.64 (1H, s), 7.77 (1H, d,J=8 Hz).

Production Example 74 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine oxalate

An achromatic crystal,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine oxalatewas obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3390, 2871, 1614, 1310, 1122, 766.

NMR (DMSO-d₆) δppm: 1.5-1.9 (2H, m), 1.9-2.9 (8H, m), 2.92 (2H, t, J=7Hz), 3.3-3.7 (1H, m), 3.43 (2H, t, J=6 Hz), 3.62 (2H, t, J=7 Hz), 7.25(1H, d, J=8 Hz), 7.39 (1H, d, J=5 Hz), 7.72 (1H, d, J=5 Hz), 7.73 (1H,s), 7.90 (1H, d, J=8 Hz).

Production Example 75 Production ofN-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamide

0.50 g of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine wasdissolved in 5 ml of methylene chloride. The obtained solution wascooled to −60° C. Thereafter, 0.27 ml of triethylamine and 0.14 ml ofacetyl chloride were added thereto, and the obtained mixture was stirredat a room temperature for 1 hour. Thereafter, water and ethyl acetatewere added to the reaction mixture, and an organic layer was thenseparated. The organic layer was washed with a saturated saline solutionand then dried over anhydrous magnesium sulfate. The solvent was thendistilled away under a reduced pressure. The residue was purified bycolumn chromatography (eluent; chloroform:methanol=50:1 to 10:1), so asto obtain 0.55 g of a yellow oil product,N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamide.

IR (neat)cm⁻¹: 3292, 2946, 1654, 1560, 1110, 757, 702.

NMR (CDCl₃) δppm: 1.5-1.7 (1H, m), 1.7-1.8 (2H, m), 1.94 (3H, s), 2.13(1H, q, J=9 Hz), 2.2-2.3 (1H, m), 2.4-2.5 (3H, m), 2.59 (1H, dd, J=2, 10Hz), 2.86 (1H, dt, J=4, 9 Hz), 2.99 (2H, t, J=7 Hz), 3.49 (2H, t, J=6Hz), 3.67 (2H, t, J=7 Hz), 4.3-4.5 (1H, m), 5.8-5.9 (1H, m), 7.22 (1H,dd, J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H, d,J=1 Hz), 7.79 (1H, d, J=8 Hz).

Production Example 76 Production ofN-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamidehydrochloride

A light brown crystal,N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)acetamidehydrochloride was obtained in the same manner as in Production Example21.

IR (KBr)cm⁻¹: 3422, 2868, 2475, 1664, 1542, 1343, 1117, 711.

NMR (CDCl₃) δppm: 1.9-2.1 (3H, m), 2.05 (3H, s), 2.3-2.4 (1H, m),2.4-2.5 (1H, m), 2.6-2.7 (1H, m), 2.8-2.9 (2H, m), 2.97 (2H, t, J=6 Hz),3.4-3.5 (1H, m), 3.51 (2H, t, J=6 Hz), 3.6-3.7 (1H, m), 3.70 (2H, t, J=6Hz), 4.6-4.8 (1H, m), 7.22 (1H, dd, J=1, 8 Hz), 7.31 (1H, d, J=5 Hz),7.46 (1H, d, J=5 Hz), 7.67 (1H, s), 7.81 (1H, d, J=8 Hz).

Production Example 77 Production ofN-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesulfonamide

A yellow oil product,N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesulfonamidewas obtained in the same manner as in Production Example 75.

IR (neat)cm⁻¹: 3270, 2927, 2856, 1320, 1148, 1110, 756.

NMR (CDCl₃) δppm: 1.6-1.8 (3H, m), 2.1-2.3 (2H, m), 2.44 (2H, t, J=7Hz), 2.50 (1H, dd, J=6, 10 Hz), 2.60 (1H, dd, J=3, 10 Hz), 2.77 (1H, dt,J=4, 9 Hz), 2.94 (3H, s), 2.99 (2H, t, J=7 Hz), 3.48 (2H, t, J=6 Hz),3.68 (2H, t, J=7 Hz), 3.9-4.0 (1H, m), 4.6-4.8 (1H, m), 7.22 (1H, dd,J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.67 (1H, d, J=1Hz), 7.79 (1H, d, J=8 Hz).

Production Example 78 Production ofN-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesulfonamideoxalate

An achromatic crystal,N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinyl)methanesulfonamideoxalate was obtained in the same manner as in Production Example 17.

IR (KBr)cm⁻¹: 3250, 2868, 1718, 1314, 1165, 1119, 707.

NMR (DMSO-d₆) δppm: 1.8-2.0 (3H, m), 2.2-2.3 (1H, m), 2.93 (2H, t, J=7Hz), 2.97 (3H, s), 3.0-3.1 (3H, m), 3.1-3.2 (1H, m), 3.2-3.3 (1H, m),3.4-3.5 (1H, m), 3.45 (2H, t, J=6 Hz), 3.63 (2H, t, J=7 Hz), 4.0-4.1(1H, m), 7.26 (1H, dd, J=1, 8 Hz), 7.40 (1H, d, J=5 Hz), 7.4-7.6 (1H,m), 7.72 (1H, d, J=5 Hz), 7.74 (1H, d, J=1 Hz), 7.90 (1H, d, J=8 Hz).

Production Example 79 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinamine

0.43 g of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-pyrrolidinamine wasdissolved in 8.6 ml of methanol. The obtained solution was cooled to 5°C. Thereafter, 0.35 ml of 37% formalin and 0.09 g of sodium borohydridewere added thereto, and the obtained mixture was stirred at a roomtemperature for 17 hours. Thereafter, 2.6 ml of 2 mol/l hydrochloricacid was added to the reaction mixture under cooling on ice, and theobtained mixture was then stirred at a room temperature for 30 minutes.Thereafter, water and ethyl acetate were added to the reaction mixture,and a water layer was then separated. After ethyl acetate was added tothe water layer, the pH of the mixture was adjusted to pH 9.5 byaddition of a 2 mol/l aqueous sodium hydroxide solution, and an organiclayer was separated. The organic layer was washed with a saturatedsaline solution and then dried over anhydrous magnesium sulfate. Thesolvent was then distilled away under a reduced pressure. The residuewas purified by column chromatography (eluent; chloroform:methanol=50:1to 10:1), so as to obtain 0.39 g of a yellow oil product,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinamine.

IR (neat)cm⁻¹: 2945, 2862, 2786, 1458, 1111, 700.

NMR (CDCl₃) δppm: 1.6-1.8 (3H, m), 1.9-2.0 (1H, m), 2.20 (6H, s),2.2-2.3 (1H, m), 2.3-2.5 (2H, m), 2.50 (1H, dt, J=8, 12 Hz), 2.7-2.8(2H, m), 2.8-2.9 (1H, m), 2.99 (2H, t, J=7 Hz), 3.49 (2H, t, J=7 Hz),3.67 (2H, t, J=7 Hz), 7.22 (1H, dd, J=1, 8 Hz), 7.28 (1H, d, J=5 Hz),7.41 (1H, d, J=5 Hz), 7.67 (1H, d, J=1 Hz), 7.79 (1H, d, J=8 Hz).

Production Example 80 Production of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinaminedihydrochloride

0.39 g of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinaminewas dissolved in 4.0 ml of ethyl acetate. Thereafter, 0.80 ml of anethyl acetate solution containing 3.25 mol/l dry hydrogen chloride wasadded to the obtained solution, and the mixture was stirred at a roomtemperature for 1 hour and then at 5° C. for 1 hour. Thereafter,precipitated crystals were collected by filtration. The crystals werewashed with ethyl acetate and then dried, so as to obtain 0.32 g of anachromatic crystal,1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-N,N-dimethyl-3-pyrrolidinaminedihydrochloride.

IR (KBr)cm⁻¹: 2936, 1437, 1101, 701.

NMR (CDCl₃) δppm: 1.9-2.1 (2H, m), 2.4-2.6 (2H, m), 2.84 (6H, s), 2.98(2H, t, J=7 Hz), 3.1-3.2 (2H, m), 3.4-3.9 (4H, m), 3.54 (2H, t, J=5 Hz),3.72 (2H, dt, J=3, 7 Hz), 4.2-4.3 (1H, m), 7.24 (1H, d, J=8 Hz), 7.35(1H, d, J=5 Hz), 7.43 (1H, d, J=5 Hz), 7.71 (1H, s), 7.84 (1H, d, J=8Hz).

Reference Example 1 Production of3-(2-(1-benzothiophene-4-yl)ethoxy)-1-propanol

2.2 g of 2-(1-benzothiophene-4-yl)-1-ethanol was suspended in 2.2 ml oftoluene and 8.8 ml of a 50% (W/V) aqueous sodium hydroxide solution.Thereafter, 4.41 g of 2-(3-chloropropoxy)tetrahydro-2H-pyran and 0.42 gof tetra-n-butyl ammonium hydrogen sulfate were added to the suspension,and the obtained mixture was then heated to reflux for 2 hours. Aftercooling, water and toluene were added to the reaction mixture, and anorganic layer was separated. The organic layer was successively washedwith water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. Subsequently, the solvent was distilledaway under a reduced pressure, so as to obtain 6.50 g of a light brownoil mixture consisting of2-(3-(2-(1-benzothiophene-4-yl)ethoxy)propoxy)tetrahydro-2H-pyran and2-(3-chloropropoxy)tetrahydro-2H-pyran.

6.50 g of this mixture was dissolved in 8.0 ml of methanol. Thereafter,8.0 ml of water and 0.70 g of p-toluenesulfonic acid monohydrate wereadded to the obtained solution. The obtained mixture was then stirred ata room temperature for 12 hours. Thereafter, ethyl acetate and asaturated sodium bicarbonate solution were added to the reactionmixture, and an organic layer was then separated. The organic layer wassuccessively washed with water and a saturated saline solution, and thendried over anhydrous magnesium sulfate. The solvent was then distilledaway under a reduced pressure. The residue was purified by columnchromatography (eluent; toluene:ethyl acetate=4:1 to 3:1), so as toobtain 1.42 g of an oil product,3-(2-(1-benzothiophene-4-yl)ethoxy)-1-propanol.

IR (neat)cm⁻¹: 3394, 2943, 2867, 1413, 1110, 761.

NMR (CDCl₃) δppm: 1.81 (2H, qn, J=6 Hz), 2.1 (1H, brs), 3.26 (2H, t, J=7Hz), 3.63 (2H, t, J=6 Hz), 3.69 (2H, t, J=7 Hz), 3.76 (2H, t, J=6 Hz),7.0-7.4 (2H, m), 7.45 (2H, s), 7.77 (1H, dd, J=2, 7 Hz).

Reference Example 2

The following compound was obtained in the same manner as in ReferenceExample 1.

3-(2-(1-benzothiophene-2-yl)ethoxy)-1-propanol

NMR (CDCl₃) δppm: 1.68 (1H, brs), 1.86 (2H, qn, J=6 Hz), 3.17 (2H, t,J=6 Hz), 3.67 (2H, t, J=6 Hz), 3.76 (4H, t, J=6 Hz), 7.07 (1H, s),7.2-7.4 (2H, m), 7.67 (1H, d, J=8 Hz), 7.77 (1H, d, J=8 Hz).

3-(2-(1-benzothiophene-3-yl)ethoxy)-1-propanol

IR (neat) cm⁻¹: 3395, 2942, 2867, 1427, 1113, 762, 732.

NMR (CDCl₃) δppm: 1.83 (2H, qn, J=6 Hz), 2.27 (1H, t, J=6 Hz), 3.13 (2H,t, J=7 Hz), 3.65 (2H, t, J=6 Hz), 3.74 (2H, t, J=6 Hz), 3.78 (2H, t, J=7Hz), 7.18 (1H, s), 7.34 (1H, dt, J=1, 7 Hz), 7.39 (1H, dt, J=1, 7 Hz),7.76 (1H, dd, J=1, 7 Hz), 7.86 (1H, dd, J=1, 7 Hz).

3-(2-(1-benzothiophene-5-yl)ethoxy)-1-propanol

IR (neat)cm⁻¹: 3398, 2939, 2866, 1438, 1110, 704.

NMR (CDCl₃) δppm: 1.82 (2H, qn, J=6 Hz), 2.29 (1H, t, J=6 Hz), 3.00 (2H,t, J=7 Hz), 3.64 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 3.73 (2H, q, J=6Hz), 7.22 (1H, dd, J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5Hz), 7.66 (1H, d, J=1 Hz), 7.80 (1H, d, J=8 Hz).

3-(2-(1-benzothiophene-6-yl)ethoxy)-1-propanol

IR (neat)cm⁻¹: 3389, 2942, 2865, 1397, 1111, 819, 693.

NMR (CDCl₃) δppm: 1.82 (2H, qn, J=6 Hz), 2.24 (1H, t, J=6 Hz), 3.00 (2H,t, J=7 Hz), 3.64 (2H, t, J=6 Hz), 3.71 (2H, t, J=7 Hz), 3.74 (2H, q, J=6Hz), 7.21 (1H, d, J=8 Hz), 7.28 (1H, d, J=5 Hz), 7.38 (1H, d, J=5 Hz),7.70 (1H, s), 7.75 (1H, d, J=8 Hz).

3-(2-(1-benzothiophene-7-yl)ethoxy)-1-propanol Reference Example 3Production of 4-(2-(3-chloropropoxy)ethyl)-1-benzothiophene

1.40 g of 3-(2-(1-benzothiophene-4-yl)ethoxy)-1-propanol was dissolvedin 7.0 ml of methylene chloride. Thereafter, 1.10 ml of thionyl chlorideand 0.05 ml of N,N-dimethylformamide were added to the obtainedsolution, and the obtained mixture was then heated to reflux for 5hours. Subsequently, the solvent was distilled away under a reducedpressure. The residue was purified by column chromatography (eluent;hexane:ethyl acetate=20:1), so as to obtain 1.43 g of a yellow oilproduct, 4-(2-(3-chloropropoxy)ethyl)-1-benzothiophene.

IR (neat)cm⁻¹: 2867, 1413, 1113, 760.

NMR (CDCl₃) δppm: 1.99 (2H, qn, J=6 Hz), 3.23 (2H, t, J=7 Hz), 3.58 (2H,t, J=6 Hz), 3.59 (2H, t, J=6 Hz), 3.75 (2H, t, J=7 Hz), 7.18 (1H, dd,J=2, 7 Hz), 7.29 (1H, t, J=7 Hz), 7.1-7.3 (2H, m), 7.45 (2H, s), 7.76(1H, dd, J=2, 8 Hz).

Reference Example 4

The following compound was obtained in the same manner as in ReferenceExample 3.

2-(2-(3-chloropropoxy)ethyl)-1-benzothiophene

NMR (CDCl₃) δppm: 2.04 (2H, qn, J=6 Hz), 3.16 (2H, t, J=7 Hz), 3.62 (2H,t, J=6 Hz), 3.66 (2H, t, J=6 Hz), 3.75 (2H, t, J=7 Hz), 7.06 (1H, s),7.25 (1H, dt, J=1, 7 Hz), 7.30 (1H, dt, J=1, 7 Hz), 7.67 (1H, dd, J=1, 7Hz), 7.77 (1H, dd, J=1, 7 Hz).

3-(2-(3-chloropropoxy)ethyl)-1-benzothiophene

IR (neat)cm⁻¹: 2865, 1427, 1115, 762, 732.

NMR (CDCl₃) δppm: 2.02 (2H, qn, J=6 Hz), 3.13 (2H, t, J=7 Hz), 3.61 (2H,t, J=6 Hz), 3.62 (2H, t, J=6 Hz), 3.79 (2H, t, J=7 Hz), 7.19 (1H, s),7.34 (1H, dt, J=1, 7 Hz), 7.39 (1H, dt, J=1, 7 Hz), 7.77 (1H, dd, J=1, 7Hz), 7.86 (1H, dd, J=1, 7 Hz).

5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene

IR (neat)cm⁻¹: 2864, 1438, 1113, 755, 701.

NMR (CDCl₃) δppm: 2.01 (2H, qn, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.59 (2H,t, J=6 Hz), 3.61 (2H, t, J=6 Hz), 3.70 (2H, t, J=7 Hz), 7.22 (1H, dd,J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.68 (1H, d, J=1Hz), 7.79 (1H, d, J=8 Hz).

6-(2-(3-chloropropoxy)ethyl)-1-benzothiophene

IR (neat)cm⁻¹: 2864, 1113, 820, 761, 695, 652.

NMR (CDCl₃) δppm: 2.00 (2H, qn, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.58 (2H,t, J=6 Hz), 3.61 (2H, t, J=6 Hz), 3.70 (2H, t, J=7 Hz), 7.21 (1H, d, J=8Hz), 7.28 (1H, d, J=5 Hz), 7.37 (1H, d, J=5 Hz), 7.72 (1H, s), 7.73 (1H,d, J=8 Hz).

7-(2-(3-chloropropoxy)ethyl)-1-benzothiophene

IR (neat)cm⁻¹: 2866, 1460, 1395, 1115, 795, 701.

NMR (CDCl₃) δppm: 2.00 (2H, qn, J=6 Hz), 3.17 (2H, t, J=7 Hz), 3.60 (4H,t, J=6 Hz), 3.82 (2H, t, J=7 Hz), 7.20 (1H, d, J=8 Hz), 7.33 (1H, t, J=8Hz), 7.35 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz), 7.70 (1H, d, J=8 Hz).

Reference Example 5 Production of3-(2-(1-benzothiophene-5-yl)ethoxy)propyl=methanesulfonate

2.03 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)-1-propanol was dissolvedin 16.8 ml of methylene chloride. Thereafter, 2.43 ml of methanesulfonylchloride, 4.37 ml of triethylamine, and 0.10 g of4-(dimethylamino)pyridine were added to the obtained solution, whilecooling on ice. The obtained mixture was stirred at the same temperaturefor 30 minutes and then at a room temperature for 12 hours. Thereafter,methyl chloride and water were added to the reaction mixture, and anorganic layer was separated. The organic layer was successively washedwith water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. The solvent was then distilled away under areduced pressure. The residue was purified by column chromatography(eluent; hexane:ethyl acetate=5:1), so as to obtain 1.40 g of3-(2-(1-benzothiophene-5-yl)ethoxy)propyl=methanesulfonate.

IR (neat) cm⁻¹: 2937, 2866, 1352, 1174, 1114, 943, 705, 529.

NMR (CDCl₃) δppm: 1.97 (2H, qn, J=6 Hz), 2.81 (3H, s), 2.98 (2H, t, J=7Hz), 3.54 (2H, t, J=6 Hz), 3.70 (2H, t, J=6 Hz), 4.26 (2H, t, J=7 Hz),7.20 (1H, dd, J=1, 8 Hz), 7.28 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz),7.65 (1H, d, J=1 Hz), 7.79 (1H, d, J=8 Hz).

Reference Example 6 Production of2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)acetic acid and2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)acetic acid (1) Production of2,4-dimethoxyphenethyl=acetate

15.0 g of 2-(2,4-dimethoxyphenyl)-1-ethanol was dissolved in 150 ml ofmethylene chloride. Thereafter, 9.32 ml of acetic anhydride, 13.8 ml oftriethylamine, and 0.10 g of 4-(dimethylamino)pyridine were added to theobtained solution, while cooling on ice. The obtained mixture wasstirred at the same temperature for 30 minutes and then at a roomtemperature for 12 hours. Thereafter, water was added to the reactionmixture. The pH of the mixture was adjusted to pH 1.5 by addition of 6mol/l hydrochloric acid, and an organic layer was separated. The organiclayer was successively washed with water and a saturated salinesolution, and then dried over anhydrous magnesium sulfate. The solventwas then distilled away under a reduced pressure. The residue waspurified by column chromatography (eluent; hexane:ethyl acetate=5:1), soas to obtain 17.2 g of an achromatic oil product,2,4-dimethoxyphenethyl=acetate.

IR (neat)cm⁻¹: 2958, 1736, 1509, 1243, 1035, 834.

NMR (CDCl₃) δppm: 2.03 (3H, s), 2.87 (2H, t, J=7 Hz), 3.80 (6H, s), 4.22(2H, t, J=7 Hz), 6.41 (1H, d, J=9 Hz), 6.46 (1H, s), 7.05 (1H, d, J=9Hz).

Also, 2,5-dimethoxyphenethyl=acetate was obtained in the same abovemanner.

IR (neat) cm⁻¹: 2952, 1736, 1502, 1226, 1048, 802, 710.

NMR (CDCl₃) δppm: 2.01 (3H, s), 2.90 (2H, t, J=7 Hz), 3.74 (3H, s), 3.76(3H, s), 4.25 (2H, t, J=7 Hz), 6.74 (3H, s).

(2) Production of 5-acetyl-2,4-dimethoxyphenethyl=acetate

17.0 g of 2,4-dimethoxyphenethyl=acetate was dissolved in 170 ml ofmethylene chloride. Thereafter, 5.93 ml of acetyl chloride and 12.1 g ofaluminum chloride were added to the obtained solution, while cooling onice. The obtained mixture was stirred at the same temperature for 1hour. Thereafter, the reaction mixture was poured into ice water, and anorganic layer was separated. The organic layer was successively washedwith water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. The solvent was then distilled away under areduced pressure. Diisopropyl ether was added to the residue, andprecipitated crystals were then collected by filtration. The obtainedcrystals were washed with diisopropyl ether and then dried, so as toobtain 13.9 g of a yellow crystal,5-acetyl-2,4-dimethoxyphenethyl=acetate.

NMR (CDCl₃) δppm: 2.01 (3H, s), 2.57 (3H, s), 2.88 (2H, t, J=7 Hz), 3.90(3H, s), 3.93 (3H, s), 4.21 (2H, t, J=7 Hz), 6.42 (1H, s), 7.68 (1H, s).

Also, 4-acetyl-2,5-dimethoxyphenethyl=acetate was obtained in the sameabove manner.

(3) Production of 5-acetyl-4-hydroxy-2-methoxyphenethyl=acetate

13.9 g of 5-acetyl-2,4-dimethoxyphenethyl=acetate was dissolved in 70 mlof acetonitrile. Thereafter, 13.9 g of aluminum chloride and 7.82 g ofsodium iodide were added to the obtained solution, while cooling on ice.The obtained mixture was stirred at 50° C. for 3 hours. Thereafter, thereaction mixture was poured into ice water, ethyl acetate was then addedto the obtained mixture, and an organic layer was then separated. Theorganic layer was successively washed with water and a saturated salinesolution, and then dried over anhydrous magnesium sulfate. The solventwas then distilled away under a reduced pressure, so as to obtain 13.3 gof a yellow oil product, 5-acetyl-4-hydroxy-2-methoxyphenethyl=acetate.

Also, 4-acetyl-5-hydroxy-2-methoxyphenethyl=acetate was obtained in thesame above manner.

(4) Production of1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone

13.3 g of the above 5-acetyl-4-hydroxy-2-methoxyphenethyl=acetate wasdissolved in 30 ml of ethanol. Thereafter, 21 ml of a 5 mol/l aqueoussodium hydroxide solution was added to the obtained solution, and theobtained mixture was stirred at a room temperature for 17 hours.Thereafter, water and ethyl acetate were added to the reaction mixture,and the pH of the obtained mixture was adjusted to pH 1 by addition of 6mol/l hydrochloric acid. Thereafter, an organic layer was separated. Theorganic layer was successively washed with water and a saturated salinesolution, and then dried over anhydrous magnesium sulfate. The solventwas then distilled away under a reduced pressure. Diisopropyl ether wasadded to the residue, and precipitated crystals were then collected byfiltration. The obtained crystals were washed with diisopropyl ether andthen dried, so as to obtain 8.30 g of a yellow crystal,1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone.

Also, 1-(2-hydroxy-4-(2-hydroxyethyl)-5-methoxyphenyl)-1-ethanone wasobtained in the same above manner.

NMR (CDCl₃) δppm: 1.6-1.8 (1H, m), 2.61 (3H, s), 2.90 (2H, t, J=7 Hz),3.8-4.1 (2H, m), 3.84 (3H, s), 6.84 (1H, s), 7.06 (1H, s), 11.98 (1H,s).

(5) Production of2-bromo-1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone

10.0 g of 1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanonewas dissolved in 100 ml of methylene chloride. Thereafter, 2.94 ml ofbromine was added dropwise to the obtained solution. The obtainedmixture was stirred at a room temperature for 1 hour. Thereafter, thereaction mixture was poured into ice water, and an organic layer wasseparated. The organic layer was successively washed with water and asaturated saline solution, and then dried over anhydrous magnesiumsulfate. The solvent was then distilled away under a reduced pressure,so as to obtain 16.4 g of a yellow oil product,2-bromo-1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone.

Also,2-bromo-1-(2-hydroxy-4-(2-hydroxyethyl)-5-methoxyphenyl)-1-ethanone wasobtained in the same above manner.

IR (neat)cm⁻¹: 3376, 2941, 1644, 1496, 1243, 1034, 757, 690.

NMR (CDCl₃) δppm: 1.5-1.8 (1H, m), 2.91 (2H, t, J=7 Hz), 3.8-4.1 (2H,m), 3.85 (3H, s), 4.40 (2H, s), 6.89 (1H, s), 7.07 (1H, s), 11.51 (1H,s).

(6) 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol

16.4 g of the above2-bromo-1-(2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl)-1-ethanone wasdissolved in 70 ml of methanol. Thereafter, 17.3 g of sodium acetate wasadded to the obtained solution, and the obtained mixture was then heatedto reflux for 5 minutes. After cooling, water and ethyl acetate wereadded to the reaction mixture, and an organic layer was separated. Theorganic layer was successively washed with water and a saturated salinesolution, and then dried over anhydrous magnesium sulfate. The solventwas then distilled away under a reduced pressure. The residue wasdissolved in 150 ml of methanol. Thereafter, 6.30 g of sodiumborohydride was dividedly added to the obtained solution, and theobtained mixture was stirred at a room temperature for 1 hour.Subsequently, 6 mol/l hydrochloric acid was added to the reactionsolution, so that the pH thereof was adjusted to pH 1. The obtainedsolution was further stirred at a room temperature for 1 hour. Thisreaction mixture was concentrated under a reduced pressure. Thereafter,water and ethyl acetate were added thereto, and an organic layer wasseparated. The organic layer was successively washed with water and asaturated saline solution, and then dried over anhydrous magnesiumsulfate. The solvent was then distilled away under a reduced pressure.The residue was purified by column chromatography (eluent:hexane:ethylacetate=4:1), so as to obtain 1.48 g of a light yellow crystal,2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol.

NMR (CDCl₃) δppm: 1.79 (1H, brs), 2.97 (2H, t, J=7 Hz), 3.84 (2H, t, J=7Hz), 3.86 (3H, s), 6.66 (1H, d, J=3 Hz), 7.03 (1H, s), 7.35 (1H, s),7.51 (1H, d, J=3 Hz).

Also, 2-(5-methoxy-1-benzofuran-6-yl)-1-ethanol was obtained in the sameabove manner.

NMR (CDCl₃) δppm: 2.04 (1H, brs), 2.98 (2H, t, J=6 Hz), 3.86 (2H, t, J=6Hz), 3.86 (3H, s), 6.68 (1H, d, J=2 Hz), 7.02 (1H, s), 7.31 (1H, s),7.55 (1H, d, J=2 Hz).

(7) Production of 2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)acetic acid

1.75 g of 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol was dissolved in amixed solution consisting of 7.0 ml of tert-butanol and 1.75 ml ofN,N-dimethylformamide. Thereafter, 2.2 g of 1-chloroacetylpiperidine and1.54 g of potassium tert-butoxide were added to the obtained solution,while cooling on ice. The obtained mixture was stirred at the sametemperature for 30 minutes and then at a room temperature for 2 hours.Thereafter, water and ethyl acetate were added to the reaction mixture.The pH of the obtained mixture was adjusted to pH 1 by addition of 6mol/l hydrochloric acid, and an organic layer was separated. The organiclayer was successively washed with water and a saturated salinesolution, and then dried over anhydrous magnesium sulfate. The solventwas then distilled away under a reduced pressure. The residue wasdissolved in 10.5 ml of a 90% aqueous ethanol solution. Thereafter, 0.91g of sodium hydroxide was added thereto, and the obtained mixture wasthen heated to reflux for 3 hours. After cooling, water and ethylacetate were added to the reaction mixture. The pH of the obtainedmixture was adjusted to pH 1 by addition of 6 mol/l hydrochloric acid,and an organic layer was separated. The organic layer was successivelywashed with water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. The solvent was then distilled away under areduced pressure. Thereafter, diisopropyl ether was added to theresidue, and precipitated crystals were then collected by filtration.The obtained crystals were washed with diisopropyl ether and then dried,so as to obtain 1.42 g of a yellow crystal,2-(2-(6-methoxy-1-benzofuran-5-yl)ethoxy)acetic acid.

IR (neat)cm⁻¹: 2939, 1734, 1426, 1252, 1200, 1148, 1094, 1022, 771.

NMR (DMSO-d₆) δppm: 2.88 (2H, t, J=7 Hz), 3.64 (2H, t, J=7 Hz), 3.82(3H, s), 4.01 (2H, s), 6.81 (1H, d, J=2 Hz), 7.22 (1H, s), 7.44 (1H, s),7.82 (1H, d, J=2 Hz).

Also, 2-(2-(5-methoxy-1-benzofuran-6-yl)ethoxy)acetic acid was obtainedin the same above manner.

NMR (DMSO-d₆) δppm: 2.90 (2H, t, J=7 Hz), 3.66 (2H, t, J=7 Hz), 3.82(3H, s), 4.02 (2H, s), 6.86 (1H, d, J=2 Hz), 7.15 (1H, s), 7.46 (1H, s),7.88 (1H, d, J=2 Hz).

Reference Example 7 Production of3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acid

(1) 29 mg of potassium hydroxide, 83 mg of tetra-n-butyl ammoniumbromide, and 5.67 ml of tert-butyl acrylate were added to 4.60 g of2-(1-benzothiophene-5-yl)-1-ethanol, and the obtained mixture was thenstirred at 45° C. to 50° C. for 2 hours. After cooling, water andtoluene were added to the reaction mixture. The pH of the mixture wasadjusted to pH 1 by addition of 6 mol/l hydrochloric acid, and anorganic layer was separated. The organic layer was washed with water andthen dried over anhydrous magnesium sulfate. The solvent was thendistilled away under a reduced pressure. The residue was purified bycolumn chromatography (eluent; hexane:ethyl acetate=5:1), so as toobtain 7.70 g of an achromatic oil product,3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acid tert-butyl.

IR (neat) cm⁻¹: 2978, 2867, 1729, 1368, 1159, 1112, 702.

NMR (CDCl₃) δppm: 1.43 (9H, s), 2.49 (2H, t, J=6 Hz), 2.99 (2H, t, J=7Hz), 3.70 (2H, t, J=6 Hz), 3.70 (2H, t, J=7 Hz), 7.21 (1H, dd, J=2, 8Hz), 7.27 (1H, dd, J=1, 5 Hz), 7.41 (1H, d, J=5 Hz), 7.6-7.7 (1H, m),7.78 (1H, d, J=8 Hz).

(2) 7.60 g of 3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acidtert-butyl was dissolved in 22.8 ml of toluene. Thereafter, 94 mg ofp-toluenesulfonic acid monohydrate was added thereto, and the obtainedmixture was heated to reflux for 6 hours. After cooling, water and ethylacetate were added to the reaction mixture, and an organic layer wasseparated. The organic layer was dried over anhydrous magnesium sulfate.The solvent was then distilled away under a reduced pressure. Theresidue was crystallized from a toluene-cyclohexane mixed solution (1:4;23 ml), so as to obtain 5.30 g of a light red crystal,3-(2-(1-benzothiophene-5-yl)ethoxy)propionic acid.

IR (KBr)cm⁻¹: 2860, 1719, 1273, 1128, 706.

NMR (CDCl₃) δppm: 2.63 (2H, t, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.73 (2H,t, J=7 Hz), 3.74 (2H, t, J=6 Hz), 7.20 (1H, dd, J=1, 8 Hz), 7.28 (1H,dd, J=1, 5 Hz), 7.41 (1H, d, J=5 Hz), 7.6-7.7 (1H, m), 7.79 (1H, d, J=8Hz).

Formulation Example 1

Component (i): A mixture consisting of 50 mg of1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol maleate(hereinafter referred to as compound A), 20 mg of lactose, 25 mg of cornstarch, and 40 mg of Avicel PH101 (manufactured by Asahi Kasei Corp.)

Component (ii): 10 mg of Kollidon CL (manufactured by BASF), 10 mg ofAvicel PH302 (manufactured by Asahi Kasei Corp.), 18 mg of lightanhydrous silicic acid, and 2 mg of magnesium stearate

Component (i) was kneaded with a 5% polyvinylpyrrolidone K30 aqueoussolution and then dried at 60° C. Thereafter, component (ii) was mixedwith the above mixture. The obtained mixture was formulated into a roundtablet with a weight of 175 mg and a diameter of 8 mm, thereby obtaininga tablet containing 50 mg of compound A.

Formulation Example 2

Component (i): A mixture consisting of 50 mg of compound A, 20 mg oflactose, and 53 mg of corn starch

Component (ii): 7 mg of Kollidon CL (manufactured by BASF), 18 mg ofAvicel PH302 (manufactured by Asahi Kasei Corp.), and 2 mg of magnesiumstearate

Component (i) was kneaded with a 5% polyvinylpyrrolidone K30 aqueoussolution and then dried at 60° C. Thereafter, component (ii) was mixedwith the above mixture. 150 mg of the obtained mixture was filled in asize-3 gelatin capsule, so as to obtain a capsule agent.

Formulation Example 3

1 g of compound A was weighed. 80 ml of a parenteral solution (JapanesePharmacopoeia) was added to the obtained compound for dissolution. A 0.1mol/l aqueous sodium dihydrogen phosphate solution and a 0.1 mol/laqueous sodium phosphate solution were added to the above solution, sothat the pH of the mixture was adjusted to pH 7.5. Thereafter, anappropriate amount of sodium chloride was added as an isotonizing agentto the obtained solution. A parenteral solution was further addedthereto, so as to obtain exactly 100 ml of a solution. This solution wasfiltrated through a membrane filter (pore size: 0.2 μm) under asepticenvironment, so as to obtain a solution used as eyedrop. The obtainedsolution was filled in a polyethylene eyedrop bottle (volume: 5 ml)under aseptic environment, and the bottle was then hermetically closed,so as to obtain an eyedrop agent containing 1 w/v % compound A.

Formulation 4

1 g of compound A was weighed. 80 ml of a parenteral solution (JapanesePharmacopoeia) was added to the obtained compound for dissolution. A 0.1mol/l aqueous potassium dihydrogen phosphate solution and a 0.1 mol/laqueous sodium dihydrogen phosphate solution were added to the abovesolution, so that the pH of the mixture was adjusted to pH 7.5.Thereafter, an appropriate amount of sodium chloride was added as anisotonizing agent to the obtained solution. A parenteral solution wasfurther added thereto, so as to obtain exactly 100 ml of a solution.This solution was filtrated through a membrane filter (pore size: 0.2μm) under aseptic environment, so as to obtain a solution used aseyedrop. The obtained solution was filled in a polyethylene eyedropbottle (volume: 5 ml) under aseptic environment, and the bottle was thenhermetically closed, so as to obtain an eyedrop agent containing 1 w/v %compound A.

INDUSTRIAL APPLICABILITY

The alkyl ether derivative represented by the general formula [1] or asalt thereof shows the effect of protecting retinal nerve cells, andthus it is useful as a preventive and/or remedy for retinal nervediseases such as glaucoma, diabetic retinopathy, retinal arteryobstruction, retinal venous obstruction, macular degeneration, andretinopathy of prematurity.

1-8. (canceled)
 9. A method for treating a retinal nerve diseasecomprising administering to a subject in need thereof an alkyl etherderivative, wherein the alkyl ether derivative is1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol or its salt.10. The method according to claim 9, wherein the alkyl ether derivativeis 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinol maleate.11. The method according to claim 9, wherein the retinal nerve diseaseis glaucoma.
 12. The method according to claim 9, wherein the retinalnerve disease is diabetic retinopathy.
 13. The method according to claim9, wherein the retinal nerve disease is retinal artery obstruction. 14.The method according to claim 9, wherein the retinal nerve disease isretinal venous obstruction.
 15. The method according to claim 9, whereinthe retinal nerve disease is macular degeneration.
 16. The methodaccording to claim 9, wherein the retinal nerve disease is retinopathyof prematurity.